CN106659675B - Topical antiviral compositions and methods of use thereof - Google Patents

Topical antiviral compositions and methods of use thereof Download PDF

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CN106659675B
CN106659675B CN201580048884.0A CN201580048884A CN106659675B CN 106659675 B CN106659675 B CN 106659675B CN 201580048884 A CN201580048884 A CN 201580048884A CN 106659675 B CN106659675 B CN 106659675B
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nitric oxide
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CN106659675A (en
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K.麦克黑尔
R.多克西
N.斯塔斯科
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NVN Liquidation Inc
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Abstract

The present invention relates generally to topical antiviral compositions and methods of use thereof.

Description

Topical antiviral compositions and methods of use thereof
Related application information
The present application claims the benefit of U.S. provisional patent application Ser. No. 62/023,587 filed on 7-11-2014 and U.S. provisional patent application Ser. No. 62/139,176 filed on 3-27-2015, the respective disclosures of which are incorporated herein by reference in their entireties.
Technical Field
The present invention relates generally to topical antiviral compositions and methods of use thereof. Methods of using the topical antiviral compositions include methods of treating and/or preventing viral infections.
Background
Viruses cause a number of diseases that can be treated locally. For example, warts can be caused by human papillomaviruses and can be treated locally. However, viruses can be difficult to treat because they invade the host cell and replicate. In addition, new strains have emerged, including antiviral resistant strains.
Summary of The Invention
It should be noted that aspects described with respect to one embodiment may be incorporated into a different embodiment, although not specifically described with respect thereto. Some embodiments relate to compositions, kits, and/or methods for treating and/or preventing a viral infection. In some embodiments, methods of treating and/or preventing a viral infection in a subject in need thereof are provided.
In some embodiments, the method comprises administering to the skin of the subject a topical composition, wherein the topical composition comprises nitric oxide-releasing active pharmaceutical ingredient in an amount of about 0.5% to about 20% by weight of the composition, thereby treating and/or preventing a viral infection in the subject.
In some embodiments, the method comprises administering to the skin of the subject a topical composition, wherein the topical composition comprises a nitric oxide-releasing active pharmaceutical ingredient that releases nitric oxide to the skin of the subject, and wherein the topical composition maintains a real-time nitric oxide concentration of at least about 7 pmol NO/mg composition for at least 1 hour after administration, as measured by a real-time in vitro release assay, thereby treating and/or preventing a viral infection in the subject.
In some embodiments, the method comprises administering to the skin of the subject a topical composition, wherein the topical composition comprises a nitric oxide-releasing active pharmaceutical ingredient that releases nitric oxide to the skin of the subject, and wherein the topical composition maintains at least about 104 pmol NO/cm for a period of at least 1 hour after administration of the skin composition to the subject 2 As measured by a real-time in vitro release assay, to treat and/or prevent a viral infection in a subject.
The foregoing and other aspects of the invention will now be described in more detail with respect to other embodiments described herein. It is to be understood that the present invention may be embodied in various forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
Brief Description of Drawings
FIG. 1 shows a schematic representation of experimental infection in rabbits.
Figure 2 shows a graph of mean ± SEM of Geometric Mean Diameter (GMD) measurements of CRPV-induced rabbit papilloma from rabbits in group a. Papillomas were induced at 2 sites with 5 μg wt-CRPV plasmid stock (+.,) and at 2 sites with 5 μg mE8-CRPV plasmid stock (≡.o.). Left sites (L1 and L2) were treated with placebo gel topically (+, o) and right sites (R1 and R2) were untreated (.sup.,. DELTA.). Each symbol represents the mean (±sem) of GMD measured weekly.
Figure 3 shows a graph of mean ± SEM of GMD measurements of CRPV-induced rabbit papilloma from rabbits in group B. Papillomas were induced at 2 sites with 5 μg wt-CRPV plasmid stock (+.,) and at 2 sites with 5 μg mE8-CRPV plasmid stock (≡.o.). Left sites (L1 and L2) were treated locally with 1% Nitricil ™ NVN (+.o.), right sites (R1 and R2) were untreated (.sup.,. DELTA.). Each symbol represents the mean (±sem) of GMD measured weekly.
Figure 4 shows a graph of mean ± SEM of GMD measurements of CRPV-induced rabbit papilloma from rabbits in group C. Papillomas were induced at 2 sites with 5 μg wt-CRPV plasmid stock (+.,) and at 2 sites with 5 μg mE8-CRPV plasmid stock (≡.o.). Left sites (L1 and L2) were treated locally (++O) with 1.6% Nitricil ™ NVN, right sites (R1 and R2) were untreated (++Delta). Each symbol represents the mean (±sem) of GMD measured weekly.
Figure 5 shows a graph of mean ± SEM of GMD measurements of CRPV-induced rabbit papilloma from rabbits in group D. Papillomas were induced at 2 sites with 5 μg wt-CRPV plasmid stock (+.,) and at 2 sites with 5 μg mE8-CRPV plasmid stock (≡.o.). The left sites (L1 and L2) were treated locally with 10% Nitricil ™ NVN (+.o.), the right sites (R1 and R2) were untreated (+.t.). Each symbol represents the mean (±sem) of GMD measured weekly.
Figure 6 shows a graph of mean ± SEM of GMD measurements of CRPV-induced rabbit papilloma from rabbits in group E. Papillomas were induced at 2 sites with 5 μg wt-CRPV plasmid stock (+.,) and at 2 sites with 5 μg mE8-CRPV plasmid stock (≡.o.). Left sites (L1 and L2) were treated locally (+.O) with 16.3% Nitricil ™ NVN, right sites (R1 and R2) were untreated (+.DELTA.). Each symbol represents the mean (±sem) of GMD measured weekly.
Figure 7 shows a graph of mean ± SEM of GMD measurements of CRPV-induced rabbit papilloma from rabbits in group F. Papillomas were induced at 2 sites with 5 μg wt-CRPV plasmid stock (+.,) and at 2 sites with 5 μg mE8-CRPV plasmid stock (≡.o.). Left sites (L1 and L2) were treated locally with placebo ointment (+, o) and right sites (R1 and R2) were untreated (.sup.,. DELTA.). Each symbol represents the mean (±sem) of GMD measured weekly.
Figure 8 shows a graph of mean ± SEM of GMD measurements of CRPV-induced rabbit papilloma from rabbits in group G. Papillomas were induced at 2 sites with 5 μg wt-CRPV plasmid stock (+.,) and at 2 sites with 5 μg mE8-CRPV plasmid stock (≡.o.). Left sites (L1 and L2) were treated locally with monophasic, 10% Nitricil ™ NVN1 ointment (+.o.), right sites (R1 and R2) were untreated (+.DELTA.). Each symbol represents the mean (±sem) of GMD measured weekly.
Figure 9 shows a graph of mean ± SEM of GMD measurements of CRPV-induced rabbit papilloma from rabbits in group H. Papillomas were induced at 2 sites with 5 μg wt-CRPV plasmid stock (+.,) and at 2 sites with 5 μg mE8-CRPV plasmid stock (≡.o.). Left sites (L1 and L2) were treated locally (++o,) with 0.3% cidofovir/cremophor (50%), right sites (R1 and R2) were untreated (/ -),. DELTA.). Each symbol represents the mean (±sem) of GMD measured weekly.
Figure 10 shows a graph of average value of rabbits ± SEM rabbit body weight (kg) in groups a-H. Body weight was plotted against time after infection with CRPV along with SEM error bars.
Figure 11 shows a graph of cumulative Nitric Oxide (NO) release over time for the formulations used in groups B, D and G.
Figure 12 shows a graph of real-time NO release over time for the formulations used in groups B and D.
Figure 13 shows a graph of cumulative NO release over time for the formulations used in groups C, E and G.
Figure 14 shows a graph of real-time NO release over time for the formulations used in groups C and E.
Figure 15 shows a graph of cumulative NO release over time for the formulations used in groups B, C, D, E and G.
FIG. 16A shows a graph of real-time NO release in pmol/mg for the formulations used in groups B, D, E and G, with rectangles representing NO release ranges for the 1 hour, 2 hours, and 4 hours periods and some embodiments of the invention.
Fig. 16B is an enlarged version of the first 1.5 hours of fig. 16A, with rectangles representing a period of 1 hour and NO release range for some embodiments of the invention.
FIG. 17 shows the concentration of the active ingredient in pmol/cm for the formulations used in groups D and E 2 Graph of the real-time NO release measured, rectangle representing time periods of 1 hour, 2 hours and 4 hours versus per cm of some embodiments of the invention 2 NO release range of (c).
Figure 18 shows a plot of papilloma size (GMD) in mm over time for the formulation used in group a. Papillomas were induced at 2 sites with 5 μg wt-CRPV plasmid stock (+., t.times.), and at 2 sites with 5 μg mE8-CRPV plasmid stock (≡o,. Times.). Left sites (L1 and L2) were treated with placebo topically (+, O) and right sites (R1 and R2) were untreated (. DELTA.T). Each symbol represents the mean (±sem) of GMD measured weekly.
Figure 19 shows a plot of papilloma size (GMD) in mm over time for the formulation used in group B. Papillomas were induced at 2 sites with 5 μg wt-CRPV plasmid stock (+., t.times.), and at 2 sites with 5 μg mE8-CRPV plasmid stock (≡o,. Times.). Left sites (L1 and L2) were treated locally with 2% of Nitricil ™ NVN formulation (+.o.), right sites (R1 and R2) were untreated (/. DELTA.). Each symbol represents the mean (±sem) of GMD measured weekly.
Figure 20 shows a plot of papilloma size (GMD) in mm over time for the formulation used in group C. Papillomas were induced at 2 sites with 5 μg wt-CRPV plasmid stock (+., t.times.), and at 2 sites with 5 μg mE8-CRPV plasmid stock (≡o,. Times.). The left sites (L1 and L2) were treated locally (+.o.) with 4% Nitricil ™ NVN formulation and the right sites (R1 and R2) were untreated (+.DELTA.). Each symbol represents the mean (±sem) of GMD measured weekly.
Figure 21 shows a plot of papilloma size (GMD) in mm over time for the formulation used in group D. Papillomas were induced at 2 sites with 5 μg wt-CRPV plasmid stock (+., t.times.), and at 2 sites with 5 μg mE8-CRPV plasmid stock (≡o,. Times.). Left sites (L1 and L2) were treated locally (+.o.) with 8% Nitricil ™ NVN formulation and right sites (R1 and R2) were untreated (/. DELTA.). Each symbol represents the mean (±sem) of GMD measured weekly.
Figure 22 shows a plot of papilloma size (GMD) in mm over time for the formulation used in group E. Papillomas were induced at 2 sites with 5 μg wt-CRPV plasmid stock (+., t.times.), and at 2 sites with 5 μg mE8-CRPV plasmid stock (≡o,. Times.). The left sites (L1 and L2) were treated locally with 10% of the Nitricil ™ NVN formulation (+.o.), the right sites (R1 and R2) were untreated (/. DELTA.). Each symbol represents the mean (±sem) of GMD measured weekly.
Figure 23 shows a plot of papilloma size (GMD) in mm over time for the formulation used in group F. Papillomas were induced at 2 sites with 5 μg wt-CRPV plasmid stock (+., t.times.), and at 2 sites with 5 μg mE8-CRPV plasmid stock (≡o,. Times.). The left sites (L1 and L2) were treated locally with imiquimod control (++o), the right sites (R1 and R2) were untreated (.sup.,. DELTA.). Each symbol represents the mean (±sem) of GMD measured weekly.
Detailed description of the preferred embodiments
The present invention will now be described more fully hereinafter. This invention may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the invention and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the present application and relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
Also as used herein, "and/or" refers to and includes any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").
Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein may be used in any combination. Furthermore, the present invention contemplates that in some embodiments of the invention, any feature or combination of features listed herein may be excluded or omitted. For purposes of illustration, if the specification states that the complex comprises components A, B and C, it is specifically intended that either or a combination of A, B or C may be omitted and abandoned.
As used herein, the transitional phrase "consisting essentially of … …" (and grammatical variants) should be construed to include the recited materials or steps and "those materials or steps that do not materially affect the basic and novel characteristics of the invention as claimed. As can be seen in the figures,In re Herz537 f.2d 549, 551-52, 190 u.s.p.q.461, 463 (CCPA 1976) (emphasized in the text), see also MPEP ≡ 2111.03. Thus, the term "consisting essentially of …" as used herein… the composition "should not be interpreted as an equivalent of" comprising ".
As used herein, when referring to a measurable value, such as an amount or concentration, etc., the term "about" means a change of up to ±20% of the specified value, such as, but not limited to, ±10%, ±5%, ±1%, ±0.5% or even ±0.1% of the specified value, as well as the specified value. For example, "about X" (where X is a measurable value) is meant to include X as well as changes of ±20%, ±10%, ±5%, ±1%, ±0.5% or even ±0.1% of X. For measurable values, the ranges provided herein can include any other range and/or individual value therein.
According to some embodiments of the invention, provided herein are methods of treating and/or preventing a viral infection. Methods of treating and/or preventing a viral infection may comprise administering to the skin of a subject a topical antiviral composition (i.e., a composition of the invention), thereby treating and/or preventing a viral infection in a subject. In some embodiments, the topical antiviral composition can be administered and/or applied to a subject's virally infected skin. In some embodiments, the methods of the invention can suppress and/or inhibit viral replication of a virus and/or enhance a local immune response in a subject.
Exemplary viral infections include, but are not limited to, cytomegalovirus (CMV), epstein-Barr virus, varicella Zoster Virus (VZV), vaccinia virus, monkey pox virus, herpes simplex virus (HSV1+2), shingles, human herpesvirus 6 (HHV-6), human herpesvirus 8 (HHV-8), papilloma virus, molluscum contagiosum, capripoxvi, smallpox, and/or coxsackievirus. In some embodiments, the viral infection may be caused by a papillomavirus, such as a human papillomavirus. Human Papillomaviruses (HPV) may be HPV types 1, 2, 3, 4, 6, 10, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and/or 59. In some embodiments, the viral infection may be caused by a herpes simplex virus, such as herpes simplex type 1 and/or herpes simplex type 2. In some embodiments, the viral infection may infect the skin, including mucous membranes, of the subject. In certain embodiments, the virus may be a human virus.
According to some embodiments of the invention, provided herein are methods of treating and/or preventing a virus-related skin condition. Methods of treating and/or preventing a virus-related skin condition may comprise administering to the skin of a subject a topical antiviral composition (i.e., a composition of the invention), thereby treating and/or preventing a virus-related skin condition in the subject. Viral-related skin conditions that may be treated and/or prevented include, but are not limited to, those associated with Boennian papulosis, varicella, butcher's wart, condyloma acuminatum, vaccinia, cytomegalovirus, diffuse shingles, herpetic eczema (Kaposi's varicella), vaccinia eczema, epidermodysplasia verrucosa, infectious erythema (fifth disease, cheek disease) farm pox, systemic vaccinia, genital herpes (herpes foreskin), buschke-L, wenstein's tumor, hand-foot-mouth disease (Coxsackie virus), heck's disease (focal epithelial hyperplasia), herpetic angina, herpes gladiatorum (bleb rash), herpes simplex, herpetic keratoconjunctivitis, herpetic whisker sore, herpetic panda, monkey pox, human T lymphocyte virus 1 infection, human superfine pox, intrauterine herpes simplex, kaposi's sarcoma, lipstz ulcer (acute vulva), soft-node, infectious warts, new-born herpes simplex, herpes zoster, deep contagious pustules, infectious cheilidermatitis, sheep pox), kohlrabi like papillomatosis, hairy mouth white spots (EBV), kohlrabi (herpes labialis), progressive vaccinia (gangrenous vaccinia, necrotic vaccinia), pseudovaccinia, recurrent respiratory papillomatosis (laryngeal papillomatosis), seal pox, varicella (chicken pox), heavy smallpox (smallpox), flat warts (flat warts), plantar warts (plantar warts), verruca vulgaris (warts), palmoplantar warts and/or shingles (shingles) -related skin conditions.
As used herein, "treatment" or "treatment of" (and grammatical variations thereof) refers to any type of treatment that imparts a benefit to a subject, and may mean that the severity of a condition in a subject is reduced, at least partially ameliorated or ameliorated, and/or achieves some reduction, alleviation or diminishment of at least one clinical symptom associated with a viral infection, and/or the presence of a delay in the progression of a viral infection and/or condition. In some embodiments, the severity of a viral infection (e.g., a viral infection caused by human papillomavirus) in a subject may be reduced as compared to the severity of a viral infection lacking the methods of the invention. In certain embodiments, the methods of the invention treat a viral infection in a subject, e.g., a viral infection affecting the skin of a subject. In some embodiments, the methods of the invention can treat viral infections by eliminating and/or reducing the size and/or appearance of at least one clinical symptom (e.g., benign lesions) associated with the viral infection. In some embodiments, the methods of the invention can treat a viral infection by eliminating at least one clinical symptom (e.g., benign lesions) associated with the viral infection for a given period of time (e.g., 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, 4, or more weeks, etc.).
In some embodiments, the topical antiviral compositions of the present invention are administered in a therapeutically effective amount. As used herein, a "therapeutically effective" amount is an amount sufficient to treat a subject (as defined herein). Those skilled in the art will appreciate that a therapeutically effective need not be complete or curative, so long as some benefit is provided to the subject. In some embodiments, a therapeutically effective amount of a topical antiviral composition of the present invention may be administered, and may include administering a therapeutically effective amount of a nitric oxide-releasing active pharmaceutical ingredient. In some embodiments, a therapeutically effective amount of nitric oxide may be administered and/or administered in the methods of the present invention. In some embodiments, the methods of the invention are practiced in a manner such that administration of the topical antiviral composition comprising nitric oxide-releasing active pharmaceutical ingredient does not result from systemic effects resulting from administration of, for example, a therapeutically effective amount of nitric oxide.
The terms "prevent," "preventing" and "prevention" (and grammatical variations thereof) refer to avoiding, reducing, and/or delaying the onset of a viral infection and/or its associated clinical symptoms in a subject, and/or reducing the severity of the onset of a viral infection and/or clinical symptoms relative to what would occur in the absence of the methods of the invention. Prevention may be complete, e.g., complete absence of viral infection and/or clinical symptoms. Prevention may also be partial such that the occurrence and/or severity of viral infection and/or clinical symptoms in a subject is less than would occur in the absence of the methods of the invention. In certain embodiments, the methods of the invention prevent a viral infection in a subject, e.g., a viral infection that can affect the skin of a subject.
In some embodiments, the topical antiviral compositions of the present invention are administered in a prophylactically effective amount. As used herein, a "prophylactically effective" amount is an amount sufficient to prevent a viral infection and/or clinical symptoms (as defined herein) in a subject. Those skilled in the art will appreciate that the level of prevention need not be complete, so long as some benefit is provided to the subject. In some embodiments, a prophylactically effective amount of the topical antiviral composition of the present invention may be administered, and may include administering a prophylactically effective amount of a nitric oxide-releasing active pharmaceutical ingredient. In some embodiments, a prophylactically effective amount of nitric oxide may be administered and/or administered in the methods of the invention. In some embodiments, the methods of the invention are practiced in a manner such that administration of the topical antiviral composition comprising nitric oxide-releasing active pharmaceutical ingredient does not result from systemic effects resulting from, for example, administration of a prophylactically effective amount of nitric oxide.
The topical antiviral composition can be topically applied to the subject using any method known to those of skill in the art. In some embodiments, the composition may be topically administered to a subject at least 1, 2, 3, or more times per day. In some embodiments, the composition may be topically administered to a subject at least 1, 2, 3, 4, 5, 6, 7, 8, or more times per week and/or month. In certain embodiments, the composition may be topically administered to the subject once daily, twice daily, every other day, every third day, once weekly, or twice weekly. In some embodiments, the composition may be administered at least once daily for a long period of time (e.g., one week, one month, two months, etc.) and/or until the viral infection and/or its associated clinical symptoms have been treated and/or prevented. In some embodiments, the composition may be applied as desired.
The present invention is useful for both veterinary and medical applications. Suitable subjects of the invention include, but are not limited to, birds and mammals. The term "bird" as used herein includes, but is not limited to, chickens, ducks, geese, quails, turkeys, pheasants, parrots, long tail parrots, budgerigars, australians parrots, canaries, and sparks. The term "mammal" as used herein includes, but is not limited to, primates (e.g., apes and humans), non-human primates (e.g., monkeys, baboons, chimpanzees, gorillas), bovine, ovine, caprine, ungulates, porcine, equine, feline, canine, lagomorpha, fin-legged, rodents (e.g., rats, hamsters, and mice), and the like. In some embodiments of the invention, the subject is a mammal, in certain embodiments the subject is a human. Human subjects include both male and female, as well as subjects of all ages, including fetal, neonatal, infant, juvenile, adolescent, adult, and geriatric subjects.
The methods of the invention may also be practiced on animal subjects, particularly mammalian subjects, such as mice, rats, dogs, cats, livestock and horses, for veterinary purposes, and/or for drug screening and drug development purposes.
In some embodiments, a subject is "in need" or "in need of" a method of the invention, e.g., a subject is a population of risk (e.g., a subject may be at risk for or more susceptible to a viral infection), a subject has a discovery generally associated with a viral infection, and/or a subject is suspected of or has been exposed to a virus. In some embodiments, a subject in need thereof has a viral infection and/or clinical signs or symptoms associated therewith that can be treated with the methods of the invention. The invention may be particularly suitable for children, adolescents, adults and/or elderly subjects.
The topical antiviral compositions of the present invention can be topically administered and/or applied to any portion of the subject's skin, including mucous membranes. For example, the composition may be topically administered to a subject's hands, fingers, feet, toes, arms, legs, trunk, anus, genitals, face, mucous membranes (including body cavities), nails, and the like. In some embodiments, the antiviral compositions of the present invention can be topically administered to at least a portion of a subject's hand, finger, foot, and/or toe. In some embodiments, the antiviral compositions of the present invention can be topically administered to at least a portion of the anus, genitalia, and/or mucosa (e.g., urethra, cervix, and/or vagina) of a subject. In some embodiments, the antiviral compositions of the present invention can be topically administered to at least a portion of the face, lips, and/or mucous membranes (e.g., nostrils, mouth, tongue, and/or pharynx) of a subject.
In some embodiments, the methods of the invention can prevent and/or reduce the appearance and/or size of benign lesions. Exemplary benign lesions include, but are not limited to, warts (e.g., verruca vulgaris), flat warts, plantar warts, subungual and/or periungual warts, anogenital warts, and the like), oral and/or laryngeal papillomas, anogenital mucosal condylomas, focal epithelial hyperplasia, kohlrabi papillomatosis, condyloma acuminatum, papillomas, molluscum contagiosum, herpetic lesions, capripoxvi, and/or vaccinia. In some embodiments, the benign lesions may be vulvar warts and/or anal warts (e.g., perianal warts). In some embodiments, the benign lesions may be non-genital warts. In some embodiments, benign lesions may be induced and/or caused by papillomaviruses, such as human papillomaviruses.
The methods of the invention can reduce the appearance and/or size of benign lesions by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or 100% as compared to the appearance and/or size of benign lesions prior to administration of the topical antiviral composition of the invention. The occurrence of benign lesions may be visually assessed, for example, but not limited to, by a subject and/or physician. The size of benign lesions can be determined using methods known to those skilled in the art. In some embodiments, the methods of the invention can prevent and/or reduce the appearance and/or size of warts.
In certain embodiments, the subject may see a decrease in size and/or appearance of benign lesions for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more days and/or weeks. In some embodiments, the method can reduce the size and/or appearance of benign lesions in the skin of a subject within 12 weeks or less, in some embodiments within 8 weeks or less, and in further embodiments within 4 weeks or less.
The methods of the invention can reduce the number of benign lesions by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or 100% as compared to the number of benign lesions prior to administration of the topical antiviral composition of the invention. The number of benign lesions may be visually assessed, for example, but not limited to, by the subject and/or physician. The number of benign lesions can be determined using methods known to those skilled in the art. In some embodiments, the methods of the invention can prevent and/or reduce the number of warts.
The methods of the invention can reduce the recurrence rate of benign lesions in a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or 100% as compared to the recurrence rate of benign lesions of the same type lacking administration of the topical antiviral composition of the invention. The recurrence rate can be determined using methods known to those skilled in the art. For example, after treatment and/or removal of benign lesions, the number of benign lesions may be visually determined after a given period of time to determine the recurrence rate. In some embodiments, the methods of the invention can reduce the recurrence rate of warts in a subject.
The method may comprise topically administering and/or applying a topical antiviral composition to virally infected skin, including mucous membranes, of a subject comprising benign lesions. In some embodiments, the virus-infected skin comprises a lesion, and the method may further comprise clearing the lesion prior to administering the topical composition to the skin of the subject. In other embodiments, the virus-infected skin comprises a lesion, and the method may not include clearing the lesion prior to administration of the topical skin composition to the subject. In some embodiments, the lesion may comprise a wart.
In certain embodiments, the methods of the invention can prevent and/or reduce the appearance and/or size of a pre-malignant and/or malignant lesion (e.g., tumor). Premalignant lesions and/or malignant lesions may be caused and/or induced by viral infection. In some embodiments, the pre-malignant lesions and/or malignant lesions may be pre-malignant and/or malignant skin lesions. In some embodiments, the premalignant and/or malignant lesions may be caused and/or caused by cervical cancer, penile cancer, anal cancer, and/or oral cancer. In some embodiments, the pre-malignant lesions and/or malignant lesions may be induced and/or caused by papillomaviruses, e.g., human papillomaviruses. In some embodiments, the methods of the invention can prevent and/or reduce the appearance and/or size of cervical intraepithelial neoplasia.
The methods of the invention can reduce the appearance and/or size of a pre-malignant and/or malignant lesion by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or more as compared to the appearance and/or size of a pre-malignant and/or malignant lesion prior to administration of the topical antiviral composition of the invention. The occurrence of a pre-malignant and/or malignant lesion may be visually assessed, for example, but not limited to, by a subject and/or physician. The size of the premalignant and/or malignant lesions may be determined using methods known to those skilled in the art.
The methods of the invention can reduce the number of premalignant and/or malignant lesions by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or 100% as compared to the number of premalignant and/or malignant lesions prior to administration of the topical antiviral composition of the invention. The number of pre-malignant lesions and/or malignant lesions may be visually assessed, for example, but not limited to, by a subject and/or physician. The number of premalignant lesions and/or malignant lesions may be determined using methods known to those skilled in the art.
The methods of the invention can reduce the recurrence rate of a premalignant and/or malignant lesion in a subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 100% as compared to the recurrence rate of the same type of premalignant and/or malignant lesion lacking administration of the topical antiviral composition of the invention. The recurrence rate can be determined using methods known to those skilled in the art. For example, after treatment and/or removal of a pre-malignant and/or malignant lesion, the number of pre-malignant and/or malignant lesions may be visually determined after a given time to determine the recurrence rate.
In some embodiments, the methods of the invention can administer basal layer nitric oxide to the epithelium of a subject. The methods of the invention can administer a therapeutically effective and/or prophylactically effective amount of nitric oxide to the basal lamina of the epithelium of a subject. In some embodiments, nitric oxide may be administered to the basal membrane of the epithelium of the subject. For the method, the epithelial layer on the subject's skin is not necessarily cleared, stripped and/or removed for administration of basal layer and/or basal membrane nitric oxide.
In some embodiments, the methods of the invention can be administered to the skin of a subject. In some embodiments, the methods of the invention can administer nitric oxide in an amount sufficient to induce apoptosis or other cellular damage in virus-infected cells. In some embodiments, the methods of the invention can administer nitric oxide in an amount sufficient to inhibit and/or prevent viral replication.
According to some embodiments of the invention, there is provided a topical antiviral composition. Exemplary compositions that may be used as topical antiviral compositions include, but are not limited to, those described in international application number PCT/US2014/019536, U.S. provisional application number 61/863,541 submitted 8/21/2013, the disclosure of each of which is incorporated herein by reference in its entirety. The topical antiviral composition may comprise a nitric oxide-releasing active pharmaceutical ingredient (NO-releasing API). In some embodiments, the topical antiviral composition does not comprise an acidified nitrite. As used herein, "acidified nitrite" refers to a nitric oxide releasing composition in which the primary mechanism of nitric oxide release is when nitrite is reduced to dinitrogen trioxide (which can dissociate into nitric oxide and nitrous oxide) in the presence of an acid. In a further embodiment of the invention, the method of the invention may be administered to the skin of a subject with nitric oxide without staining the skin of the subject. For example, the methods of the invention can be administered to the skin of a subject with nitric oxide without staining the skin of the subject with yellow, brown, and/or black.
As used herein, "nitric oxide-releasing active pharmaceutical ingredient" and "NO-releasing API" refer to compounds or other compositions that provide nitric oxide to the skin of a subject, but not gaseous nitric oxide. In some embodiments, the NO-release API is also not an acidified nitrite. In some embodiments, the NO-releasing API comprises a nitric oxide-releasing compound, hereinafter referred to as "NO-releasing compound". The NO-releasing compound comprises at least one NO donor, which is a functional group that can release nitric oxide under certain conditions.
Any suitable NO-releasing compound may be used. In some embodiments, the NO-releasing compound comprises a small molecule compound comprising a NO donor group. As used herein, a "small molecule compound" is defined as a compound having a molecular weight of less than 500 daltons, and includes organic and/or inorganic small molecule compounds. In some embodiments, the NO-releasing compound comprises a macromolecule comprising NO donor groups. "macromolecule" is defined herein as any molecule having a molecular weight of 500 daltons or more. Any suitable macromolecule may be used, including crosslinked or non-crosslinked polymers, dendrimers, metal compounds, organometallic compounds, inorganic-based compounds, and other macromolecular scaffolds. In some embodiments, the macromolecules have a nominal diameter ranging from about 0.1 nm to about 100 μm, and may include an aggregation of two or more macromolecules, whereby the macromolecular structure is further modified with NO donor groups.
In some embodiments, the NO-releasing compound comprises a diazeniumdiolate functional group as NO donor. Diazeniumdiolate functional groups can generate nitrogen oxides under certain conditions, such as when exposed to water. As another example, in some embodiments, the NO-releasing compound comprises a nitrosothiol functional group as NO donor. The NO donor may generate nitric oxide under certain conditions, such as when exposed to light. Examples of other NO donor groups include nitrosamines, hydroxynitrosamines, hydroxylamines, and hydroxyureas. Any suitable combination of NO donors and/or NO-releasing compounds may also be used in the second compositions described herein. In addition, the NO donor may be bound into or to the small or large molecule by covalent and/or non-covalent interactions.
The NO-releasing macromolecules may be in the form of NO-releasing particles, such as those described in U.S. patent No. 8,282,967, U.S. patent No. 8,962,029, or U.S. patent No. 8,956,658, the disclosures of which are incorporated herein by reference in their entirety. Other non-limiting examples of NO-releasing compounds include NO-releasing zeolites as described in U.S. patent publication nos. 2006/0269620 or 2010/0331968; NO-releasing Metal Organic Frameworks (MOFs) as described in U.S. patent application publication nos. 2010/023912 or 2011/0052650; NO-releasing multi-donor compounds as described in international application No. PCT/US2012/052350 entitled "tunable nitric oxide-releasing macromolecules with multiple nitric oxide donor structures"; NO-releasing dendrimers or metal structures as described in us publication No. 2009/0214618; a nitric oxide releasing coating as described in U.S. publication 2011/0086234; and compounds as described in U.S. publication No. 2010/0098733. The disclosure of each reference in this paragraph is incorporated by reference in its entirety. In addition, NO-releasing macromolecules can be manufactured as described in international application number PCT/US2012/022048 entitled "temperature controlled sol-gel co-condensation," filed on 1 month 20 2012, the disclosure of which is incorporated herein by reference in its entirety.
As an example, in some embodiments of the invention, the nitric oxide-releasing active pharmaceutical ingredient may comprise precipitated silica loaded with NO. The NO-loaded precipitated silica may be formed from a nitric oxide donor modified silane monomer into a co-condensed siloxane network. In one embodiment of the invention, the nitric oxide donor may be N-diazeniumdiolate. In some embodiments of the invention, the nitric oxide-releasing active pharmaceutical ingredient may comprise, consist essentially of, or consist of a cocondensated siloxane network comprising diazeniumdiolate (e.g., N-diazeniumdiolate).
In some embodiments, the nitric oxide donor may be formed from an aminoalkoxysilane by a pre-charging method, and the cocondensated siloxane network may be synthesized from the condensation of a silane mixture comprising an alkoxysilane and an aminoalkoxysilane to form a nitric oxide donor modified cocondensated siloxane network. As used herein, "pre-loading method" means that the aminoalkoxysilane is "pre-treated" or "pre-loaded" with nitrogen oxide prior to co-condensation with the alkoxysilane. In some embodiments, the pre-loading of the nitric oxide may be achieved by chemical means. In another embodiment, a "pre-load" method may be used to create a co-condensed siloxane network and material that is more densely functionalized with NO donors. In some embodiments of the present invention, the nitric oxide-releasing active pharmaceutical ingredient may comprise, consist essentially of, or consist of a co-condensed silica network synthesized from the condensation of a silane mixture comprising an alkoxysilane and at least one aminoalkoxysilane having a diazeniumdiolate (e.g., N-diazeniumdiolate) substituted amine.
The co-condensed siloxane network can be silica particles having a uniform size, a collection of silica particles having various sizes, amorphous silica, fumed silica, nanocrystalline silica, ceramic silica, colloidal silica, silica coatings, silica films, organically modified silica, mesoporous silica, silica gel, bioactive glass, or silica in any suitable form or state.
In some embodiments, the alkoxysilane is a tetraalkoxysilane having the formula Si (OR) 4, wherein R is an alkyl group. The R groups may be the same or different. In some embodiments, the tetraalkoxysilane is selected from tetramethyl orthosilicate (TMOS) or tetraethyl orthosilicate (TEOS). In some embodiments, the aminoalkoxysilane has the formula: r '- (NH-R') n-Si (OR) 3, wherein R is alkyl, R 'is alkylene, branched alkylene OR aralkylene, n is 1 OR 2, and R' is selected from alkyl, cycloalkyl, aryl and alkylamine.
In some embodiments, the aminoalkoxysilane may be selected from the group consisting of N- (6-aminohexyl) aminopropyl trimethoxysilane (AHAP 3), N- (2-aminoethyl) -3-aminopropyl trimethoxysilane (AEAP 3), (3-trimethoxysilylpropyl) di-ethylenetriamine (DET 3), (aminoethylaminomethyl) phenethyl trimethoxysilane (AEMP 3), [3- (methylamino) propyl ] trimethoxysilane (MAP 3), N-butylamino-propyl trimethoxysilane (N-BAP 3), t-butylamino-propyl trimethoxysilane (t-BAP 3), N-ethylaminoisobutyl trimethoxysilane (EAiB 3), N-phenylamino-propyl trimethoxysilane (PAP 3), and N-cyclohexylaminopropyl trimethoxysilane (cHAP 3).
In some embodiments, the aminoalkoxysilane has the formula: NH [ R '-Si (OR) 3]2, wherein R is alkyl and R' is alkylene. In some embodiments, the aminoalkoxysilane may be selected from the group consisting of bis (3-triethoxysilylpropyl) amine, bis [3- (trimethoxysilyl) propyl ] amine, and bis [ (3-trimethoxysilyl) propyl ] ethylenediamine.
In some embodiments, the aminoalkoxysilane is preloaded to release NO and the amino group is substituted with diazeniumdiolate as described herein. Thus, in some embodiments, the aminoalkoxysilane has the formula: r' -N (NONO-X) + )-R'-Si(OR) 3 Wherein R is alkyl, R 'is alkylene or aralkylene, R' is alkyl or alkylamine, and X+ is a cation selected from Na+, K+ and Li+.
The composition of the siloxane network (e.g., the amount or chemical composition of the aminoalkoxysilane) and the nitric oxide loading conditions (e.g., solvents and bases) can be varied to optimize the amount and duration of nitric oxide release. Thus, in some embodiments, the composition of the silica particles may be modified to adjust the half-life of NO released from the silica particles.
In another embodiment, the amino group of the aminoalkoxysilane is substituted with diazeniumdiolate and the aminoalkoxysilane has the formula R "-N (NONO-x+) -R' -Si (OR) 3, wherein: r is alkyl, R 'is alkylene or aralkylene, R' is alkyl or alkylamine, and X+ is a cation selected from Na+ and K+.
In certain embodiments, the NO-release API may comprise a co-condensed silica network comprising diazeniumated amino ethyl amino propyl trimethoxysilane (AEAP 3) and tetramethyl orthosilicate (TMOS) and/or a co-condensed silica network comprising diazeniumated amino ethyl amino propyl trimethoxysilane (AEAP 3) and tetraethyl orthosilicate (TEOS). In some embodiments, the NO-release API may include a co-condensed silica network comprising diazeniumated methylaminopropyl trimethoxysilane (MAP 3) and tetramethyl orthosilicate (TMOS) and/or a co-condensed silica network comprising diazeniumated methylaminopropyl trimethoxysilane (MAP 3) and tetraethyl orthosilicate (TEOS).
In some embodiments of the present invention, the particle size of the NO-release API may range from about 20 nm to about 20 μm or any range therein, such as, but not limited to, from about 100 nm to about 20 μm or from about 1 μm to about 20 μm. The particle size may be tailored to minimize or prevent toxicity and/or penetration of the epidermis (or damage to the dermis) and into blood vessels. In particular embodiments, the particle size is distributed around an average particle size of less than 20 μm or any range therein, and the size may allow the particles to enter the follicle. In some embodiments, the NO-release API may have a particle size distributed around an average particle size of about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 μm. In further embodiments, the NO-release API may have a particle size distributed around an average particle size of less than 10 μm, or any range therein, such as, but not limited to, about 2 μm to about 10 μm or about 4 μm to about 8 μm. In other embodiments, the particle size may be distributed around an average particle size of greater than 20 μm, or any range therein, and the size may prevent particles from entering the follicle. In yet further embodiments, a mixture of particles having an average particle size distributed about 2 or more average particle sizes may be provided. The NO-release API may be micronized (e.g., ball milled and/or jet milled). Methods for providing the desired particle size and/or micronization include, but are not limited to, those described in U.S. patent application publication No. 2013/0310533, which is incorporated herein by reference in its entirety.
In some embodiments, the NO-release API may be present in the topical antiviral composition in an amount of about 0.5% to about 25% by weight of the composition. For example, in some embodiments, the NO-releasing API may be present in the compositions of the present invention in an amount of from about 0.5% to about 20%, from about 0.5% to about 5%, from about 1% to about 20%, from about 1% to about 10%, from about 1% to about 8%, from about 1% to about 20%, from about 5% to about 15%, or from about 2% to about 6% by weight of the composition. In certain embodiments, the nitric oxide-releasing active pharmaceutical ingredient may be present in the compositions of the present invention in an amount of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% by weight of the composition.
The compositions of the present invention may comprise NO-releasing API and may store and/or release nitric oxide in an amount of from about 0.05% to about 10% by weight of the composition, such as, but not limited to, from about 0.15% to about 2%, from about 0.15% to about 1%, from about 0.3% to about 1.2%, from about 0.15% to about 6%, from about 1% to about 10%, from about 3% to about 6%, or from about 1% to about 5% by weight of the composition. In certain embodiments, the compositions of the present invention may comprise a nitric oxide-releasing active agent and may store and/or release nitric oxide in an amount of about 0.15%, 0.3%, 0.6%, 0.9%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.25%, 3.5%, 3.75%, 4%, 4.25%, 4.5%, 4.75%, 5%, 5.25%, 5.5%, 5.75%, 6%, 6.25%, 6.5%, 6.75%, 7.25%, 7.5%, 7.75%, 8%, 8.25%, 8.5%, 8.75%, 9.25%, 9.5%, 9.75% or 10% by weight of the composition. The amount of nitric oxide released can be determined using a real-time in vitro release assay. In some embodiments, nitric oxide release may be measured using a chemiluminescent nitric oxide analyzer.
The composition of the present invention may provide and/or allow for NO release over a prolonged period of time. In some embodiments, the compositions of the invention may provide and/or allow sustained NO release for about 1 hour or more, such as, but not limited to, about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more hours, following administration of the topical composition to a subject. In some embodiments, the composition may provide sustained NO release for at least about 1, 2, 3, 4, or 5 hours after administration of the topical composition to a subject.
In some embodiments, the topical antiviral compositions of the present invention can provide a release rate of from about 1 to about 5,000 pmol NO/mg/s of the composition for a defined period of time after administration of the composition to a subject. All nitric oxide release described herein, including those described with respect to the time period following administration to a subject, are mentioned with respect to the real-time in vitro release test. The in vivo release of nitric oxide (i.e., nitric oxide release when the topical antiviral composition of the present invention is administered to a subject) may vary from subject to whom the topical antiviral composition is administered. In some embodiments, the in vivo release of nitric oxide may vary depending on the particular embodiment of the topical antiviral composition. However, it is believed that the differences in the in vitro release of the topical antiviral compositions of the present invention will be reflected in the release of nitric oxide when the topical composition is administered to a subject. Thus, for clarity, reference to nitric oxide release with respect to embodiments of the topical antiviral compositions of the present invention will refer to in vitro release of the composition unless specifically stated to nitric oxide release as when administered to a subject. The time point zero or initial time point of the in vitro release test may be related to the time of administration to the subject, all subsequent real-time points corresponding to a certain time after administration.
In some embodiments, the composition may release about 1 to about 10, about 1 to about 100, about 100 to about 1000, about 1000 to about 4,000, or about 2,500 to about 5,000 pmol NO/mg composition at 1 hour, 45, 30, 15, 5, 4, 3, 2, or 1 minute, as measured by in vitro release. In some embodiments, the composition may release an average of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100 or more pmol NO/mg composition at 24, 20, 15, 10, 5, 4, 3, 2 or 1 hour, as measured by in vitro release.
In some embodiments, the NO release values provided herein may comprise variations typically associated with the manufacture of NO-release APIs. For example, a change in NO release can be seen between samples in the same batch and/or in different batches. In some embodiments, the variation in NO release between samples in the same batch and/or different batches may range from about 0% to about 15% and the variation may be included in the NO release values described herein. In some embodiments, the variation in NO release between samples in the same batch and/or different batches may range from about 10% to about 15% and the variation may be included in the NO release values described herein.
In some embodiments, the composition may release from about 1 to about 10, about 1 to about 100, about 100 to about 1000, about 1000 to about 4,000, or about 2,500 to about 5,000 pmol NO per mg of composition 0.5, 1 hour, 45, 30, 15, 5, 4, 3, 2, or 1 minute after administration of the composition to a subject. In some embodiments, the composition may release an average of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100 or more pmol NO/ mg composition 24, 20, 15, 10, 5, 4, 3, 2 or 1 hour after administration of the composition to a subject.
The topical antiviral compositions of the present invention can provide sustained NO release for at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more hours as measured by in vitro release, and the composition can have an average range of about 1 to about 500 pmol NO per mg of the composition of NO release during sustained release, for example, but not limited to, about 10 to about 50, about 50 to about 200, about 100 to about 500, about 300 to about 500, about 1 to about 10, or about 1 to about 3 pmol NO per mg of the composition.
The topical antiviral compositions of the present invention can provide sustained NO release for at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more hours after administration of the composition to a subject, and the composition can have an average NO release ranging from about 1 to about 500 pmol NO/mg composition during sustained release, such as, but not limited to, about 10 to about 50, about 50 to about 200, about 100 to about 500, about 300 to about 500, about 1 to about 10, or about 1 to about 3 pmol NO/mg composition.
In some embodiments of the invention, the topical antiviral composition of the invention maintains a real-time NO concentration of greater than 5 pmol NO/mg for a period of at least 4 hours, maintains a real-time NO concentration of greater than 6 pmol NO/mg for a period of at least 2 hours, and/or maintains a real-time NO concentration of greater than 7 pmol NO/mg for a period of at least 1 hour, as measured by in vitro release. In some embodiments, the topical antiviral compositions of the present invention can maintain a real-time NO concentration of at least about 5 pmol NO/mg or more (e.g., 10, 20, 30, 40, 50, 100, 150, 200, 250, 500, 1000, 2000 pmol NO/mg composition or more) for a period of at least 1 hour or more (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5 hours or more), as measured by in vitro release.
In particular embodiments of the invention, the topical antiviral composition of the invention maintains a real-time NO concentration in the range of about 5 pmol to about 4000 pmol NO/mg for a period of at least 4 hours, maintains a real-time NO concentration in the range of about 6 to about 4000 pmol NO/mg for a period of at least 2 hours, and/or maintains a real-time NO concentration in the range of about 7 to about 4000 pmol NO/mg for a period of at least 1 hour, as measured by in vitro release.
In some embodiments of the invention, the topical antiviral composition of the invention maintains greater than 74 pmol NO/cm 2 For a period of at least 4 hours, maintaining a real-time NO concentration of greater than 89 pmol NO/cm 2 For a period of at least 2 hours, and/or to maintain a real-time NO concentration of greater than 104 pmol NO/cm 2 For a period of at least 1 hour, as measured by in vitro release. In a specific embodiment of the present invention, the topical antiviral composition of the present invention maintains about 74 pmol NO/cm 2 About 59,520 pmol NO/cm 2 For a period of at least 4 hours at a range of about 89 to about 59,520 pmol NO/cm 2 For a period of at least 2 hours, and/or from about 104 to about 59,520 pmol NO/cm 2 For a period of at least 1 hour, as measured by in vitro release.
In some embodiments, the topical antiviral compositions of the present invention can provide a cumulative NO release of at least about 10 nmol NO/mg composition 24 hours or less (e.g., 24, 20, 15, 10, 5, 4, 2, or 1 hour) after administration of the composition to a subject. The topical antiviral composition can have a cumulative NO release ranging from about 10 to about 50, about 10 to about 100, about 100 to about 1000, about 250 to about 750, about 500 to about 750, about 50 to about 1000, about 100 to about 1500, about 200 to about 1000, about 100 to about 500, or about 500 to about 1000 nmol NO per mg of the composition 24 hours or less after administration of the composition to a subject.
In some embodiments, the topical antiviral compositions of the present invention provide a cumulative NO release ranging from about 180 nmol NO/mg to about 1000 nmol NO/mg within 24 hours after administration of the composition to a subject. In some embodiments of the invention, the topical antiviral composition of the invention provides a cumulative NO release of greater than 180 nmol NO/mg within 24 hours after administration of the composition to a subject, while maintaining a real-time NO concentration of greater than 5 pmol NO/mg for a period of at least 4 hours, as measured by in vitro release. In some embodiments, the topical antiviral compositions of the present invention provide a cumulative NO release ranging from about 90 nmol NO/mg to about 450 nmol NO/mg within 4 hours after administration of the composition to a subject.
In some embodiments, the topical antiviral compositions of the present invention release half of the NO released from the composition in about 9 minutes or more based on total NO release measured by in vitro release over 24 hours. In some embodiments, the topical antiviral composition may release half of the NO released from the composition within about 10, 20, 30, 40, 50, or 60 minutes, or 2, 3, 4, 5, 6, 7, or 8 hours or more, based on total NO release measured by in vitro release over 24 hours. In some embodiments, the topical antiviral compositions of the present invention release half of the NO released from the composition within a range of about 9 minutes to 8 hours, based on total NO release measured by in vitro release over 24 hours.
In some embodiments, the topical antiviral compositions of the present invention provide a maximum concentration of NO release (Cmax) of greater than 160 pmol NO/mg based on total NO release measured by in vitro release at 24 hours. In some embodiments, the topical antiviral compositions of the present invention can provide a Cmax of NO release of about 175, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500 pmol NO/mg or more based on total NO release measured by in vitro release over 24 hours. In some embodiments, the topical antiviral compositions of the present invention provide a maximum concentration of NO released ranging from about 160 pmol NO/mg to about 3500 pmol NO/mg. In some embodiments, the topical antiviral compositions of the present invention provide a maximum concentration of NO release of greater than 160 pmol NO/mg and release half of the NO released from the composition in about 9 minutes or more based on total NO release measured by in vitro release over 24 hours.
In particular embodiments of the invention, the topical antiviral composition provides a maximum concentration of NO release of at least about 3000 pmol NO/mg, releases at least about 900 nmol NO/mg within 24 hours, and/or releases half of the NO release within about 9 minutes, based on total NO release measured by in vitro release over 24 hours. In particular embodiments of the invention, the topical antiviral composition provides a maximum concentration of NO release of at least about 13 pmol NO/mg, releases at least about 300 nmol NO/mg within 24 hours, and/or releases half of the NO release within about 420 minutes, based on total NO release measured by in vitro release over 24 hours. In a further embodiment, the topical antiviral composition has a real-time NO concentration of at least 5 pmol NO/mg at 4 hours, as measured by in vitro release. In particular embodiments of the invention, the topical antiviral composition provides a maximum concentration of NO release ranging from about 12 pmol NO/mg to about 3200 pmol NO/mg, a real-time NO concentration of at least 5 pmol NO/mg at 4 hours, a release ranging from about 300 nmol NO/mg to about 1000 nmol NO/mg NO within 24 hours, and/or a half NO release within about 9 minutes to about 420 minutes, based on total NO release measured by in vitro release over 24 hours.
In some embodiments, the topical antiviral compositions of the present invention can maintain at least about 70 pmol NO/cm after administration of the composition to a subject 2 Or more (e.g., 75, 100, 150, 200, 250, 500, 1000, 2000, 3000, 4000, 5000, 6000, 7000 pmol NO/cm) 2 Or more) for a period of at least 0.5 hours or more (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5 hours or more), as measured by in vitro release. In some embodiments of the invention, the topical antiviral composition of the invention maintains greater than 70 pmol NO/cm 2 For a period of at least 4 hours, as measured by in vitro release.
In some embodiments, the topical antiviral combinations of the inventionThe compositions may provide at least about 4500 nmol NO/cm 24 hours or less (e.g., 24, 20, 15, 10, 5, 4, 2, or 1 hour) after administration of the composition to the subject 2 (e.g., 5000, 6000, 7000, 8000, 9000, 10000, 11000, 12000, 13000, 14000 nmol NO/cm) 2 Or more) accumulated NO release. In some embodiments, the topical antiviral compositions of the present invention provide a range of about 4500 nmol NO/cm within 24 hours after administration of the composition to a subject 2 -about 14000 nmol NO/cm 2 Is associated with the accumulated NO release. In some embodiments of the invention, the topical antiviral composition of the invention provides greater than 4500 nmol NO/cm within 24 hours after administration of the composition to a subject 2 Is controlled while maintaining greater than 70 pmol NO/cm 2 For a period of at least 4 hours, as measured by in vitro release. In some embodiments, the topical antiviral compositions of the present invention provide a range of about 1300 nmol NO/cm within 4 hours after administration of the composition to a subject 2 -about 14000 nmol NO/cm 2 Is associated with the accumulated NO release.
In some embodiments, the topical antiviral compositions of the present invention can have at least about 10 pmol NO/cm 0.5 hours or more (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5 hours or more) after administration of the composition to a subject 2 Or more (e.g., 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 pmol NO/cm) 2 Or more) real-time NO concentration. In some embodiments, the topical antiviral compositions of the present invention provide at least 100 pmol NO/cm at 0.5 hours 2 At least 50 pmol NO/cm at 1 hour 2 At least 40 pmol NO/cm at 2 hours 2 At least 25 pmol NO/cm at 3 hours 2 And/or at least 20 pmol NO/cm at 4 hours 2 Each as measured by in vitro release. In some embodiments, the topical antiviral compositions of the present invention provide at least 130 pmol NO/cm at 0.5 hours 2 At least 115 pmol NO/cm at 1 hour 2 At least 90 pmol NO/cm at 2 hours 2 At least 90 pmol NO/cm at 3 hours 2 A kind of electronic deviceAt least 80 pmol NO/cm at 4 hours 2 Each as measured by in vitro release.
In some embodiments, the topical antiviral compositions of the present invention provide at least 800 pmol NO/cm at 0.5 hours 2 At least 500 pmol NO/cm at 1 hour 2 At least 200 pmol NO/cm at 2 hours 2 At least 100 pmol NO/cm at 3 hours 2 And/or at least 50 pmol NO/cm at 4 hours 2 Each as measured by in vitro release.
In some embodiments, the topical antiviral compositions of the present invention provide greater than 2400 pmol NO/cm 2 NO release maximum concentration of (c). In some embodiments, the topical antiviral compositions of the present invention provide a range of about 2400 pmol NO/cm 2 About 47000 pmol NO/cm 2 NO release maximum concentration of (c). In some embodiments, the topical antiviral compositions of the present invention provide greater than 2400 pmol NO/cm based on total NO release measured by in vitro release at 24 hours 2 And release half of the NO released from the composition within 10 minutes or more.
In a specific embodiment of the present invention, the topical antiviral composition provides at least about 47000 pmol NO/cm based on total NO release measured by in vitro release at 24 hours 2 Is released at a maximum concentration of NO of at least about 13000 nmol NO/cm over a 24 hour period 2 And/or release half of the NO release in about 9 minutes. In a specific embodiment of the present invention, the topical antiviral composition provides at least about 190 pmol NO/cm based on total NO release measured by in vitro release at 24 hours 2 Is released at a maximum concentration of NO of at least about 4600 nmol NO/cm over a 24 hour period 2 And/or release half of the NO in about 420 minutes. In a further embodiment, the topical antiviral composition has at least 70 pmol NO/cm at 4 hours 2 As measured by in vitro release. In a specific embodiment of the present invention, the topical antiviral composition provides a range of about 190 pmol NO/cm based on total NO release measured by in vitro release at 24 hours 2 About 47000 pmol NO/cm 2 At least 70 pmol NO/cm at 4 hours 2 Is released within about 4600 nmol NO/cm in 24 hours 2 About 47000 nmol NO/cm 2 And/or release half of the NO release in a range of about 9 minutes to about 420 minutes.
The efficacy of the nitric oxide releasing product may be related not only to the amount of nitric oxide released, but also to its release rate. Thus, certain embodiments of the present invention may utilize a composition having an average release rate of 600 nmol NO/mg hr during about 5 minutes and in some embodiments, 4.7 minutes as measured by in vitro release 0.5 Or greater, 900 nmol NO/mg hr 0.5 Or greater, 2500 nmol NO/mg hr 0.5 Or greater, 4000 nmol NO/mg hr 0.5 Or greater or 4500 nmol NO/mg hr 0.5 Or larger products.
The pH of the compositions of the present invention may range from about 3 to about 11. In some embodiments, the pH of the composition may range from about 3 to about 5, from about 3.5 to about 4.5, from about 5 to about 7, from about 5.5 to about 6.5, from about 3.5 to about 6.5, from about 6 to about 10, from about 6 to about 7, from about 7 to about 10, from about 7 to about 9, from about 7 to about 8, from about 7.5 to about 8, or from about 8 to about 9. In certain embodiments, the pH of the composition may be about 3, 4, 5, 6, 7, 8, 9, 10, or 11. The pH of the composition may be determined prior to administration to the subject and/or may be determined upon application to the skin of the subject. In some embodiments wherein the compositions of the invention comprise two or more portions and/or phases, the pH may be determined when the two or more portions and/or phases are combined and/or mixed before and/or after administration to the skin of a subject. In certain embodiments, the pH of the composition is measured prior to administration to the subject's skin but after all parts and/or phases of the composition.
The pH can be measured using known methods. The pH of the composition of the invention may be determined before and/or after administration and/or after the first and second parts of the composition are combined once a steady state pH is reached. Alternatively or additionally, the pH of the compositions of the present invention may be measured after a defined period of time, such as, but not limited to, after about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 minutes or more. In some embodiments, the pH of the compositions of the invention can be measured in vitro. Alternatively or additionally, the pH of the composition of the invention may be measured after administration to a subject, e.g., the skin surface pH may be measured after administration of the composition of the invention to the skin of a subject.
The composition of the present invention may comprise at least two parts. The at least two portions may be combined prior to, during, and/or after administration to a subject to form an antiviral composition of the invention. In some embodiments, the compositions of the present invention comprise a first portion comprising a first composition and a second portion comprising a second composition.
In some embodiments, the first and second compositions can be combined by mixing, stirring, blending, dispersing, milling, homogenizing, applying to the same area or region, and the like. In some embodiments, the first and second compositions may be mixed and/or admixed prior to, during, and/or after administration to the skin of a subject. In some embodiments, the first composition and the second composition may be combined by applying one or more layers of the second composition to the subject and then applying one or more layers of the first composition to the subject, or vice versa, to form the topical antiviral composition of the invention.
The second composition may comprise NO-release API. In some embodiments, the compositions of the present invention may include a first portion comprising a first composition, which may be in the form of a hydrogel. As used herein, "hydrogel" refers to a hydrophilic gel comprising a gel matrix and water. In some embodiments, the first composition may comprise at least one polyol, at least one tackifier, and water. In some embodiments, the first composition may comprise at least one polyol, at least one tackifier, water, at least one additional solvent (i.e., at least one solvent other than water), a buffer and/or buffer, an emollient, and optionally a preservative.
Exemplary polyols that may be present in the first composition include, but are not limited to, glycerin, propylene glycol, polyethylene glycol, polypropylene glycol, triethylene glycol, neopentyl glycol, butylene glycol, polyethylene glycol, sorbitol, arabitol, erythritol, HSH, isomalt (isopall), lactitol, maltitol, mannitol, xylitol, threitol, ribitol, galactitol, fucitol, iditol, inositol, heptatol, and any combination thereof. In some embodiments, the first composition comprises glycerin, such as, but not limited to, anhydrous glycerin.
The polyol may be present in the first composition in an amount of from about 1% to about 30% by weight of the first composition or any range and/or individual value therein, such as, but not limited to, from about 1% to about 20%, from about 1% to about 10%, from about 5% to about 10%, or from about 5% to about 15% by weight of the first composition. In certain embodiments, the polyol may be present in the first composition in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30% by weight of the first composition or any range and/or individual value therein.
Exemplary tackifiers that may be present in the first composition include, but are not limited to, carboxypolyethylene; polyacrylic acid polymers such as polyacrylic acid, polyacrylate polymers, crosslinked polyacrylic acid, and mixtures thereof; cellulose ethers such as hydroxyalkyl cellulose polymers such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, and mixtures thereof; a methacrylate ester; polyvinylpyrrolidone; crosslinked polyvinylpyrrolidone; polyvinylpyrrolidone-vinyl acetate copolymer; polyvinyl alcohol; polyethylene oxide; polyethylene glycol; polyvinyl alkyl ether-maleic acid copolymer; a carboxyvinyl polymer; a polysaccharide; gums such as sodium alginate, carrageenan, xanthan gum, locust gum, acacia, guar gum, pullulan, agar, chitin, chitosan, pectin, karaya gum, zein, hordein, gliadin, locust bean gum, tragacanth and mixtures thereof; proteins such as collagen, whey protein isolate, casein, milk protein, soy protein, gelatin and mixtures thereof; starches such as maltodextrin, amylose, high amylose starch, corn starch, potato starch, rice starch, tapioca starch, pea starch, sweet potato starch, barley starch, wheat starch, waxy corn starch, modified starches (e.g., hydroxypropylated high amylose starch), dextrin, levan, elsinan, gluten and mixtures thereof; bentonite; calcium stearate; ceratonia; colloidal silica; dextrin; hydroxypropyl methylcellulose; polycarbophil; kaolin; soapstone; sorbitan esters; sucrose; sesame oil; tragacanth; potassium alginate; povidone; sodium starch glycolate; phospholipids and any combination thereof.
In some embodiments, the first composition may comprise a carboxypolyethylene, such as, but not limited to, carbopol under the trade name Lubrizol Corporation from Wickliffe, ohio ® Those commercially available. Exemplary Carbopol which may be present in the first composition ® Polymers include, but are not limited to, carbopol ® 974P NF polymers (e.g., homopolymers of type A, type B and/or type C), carbopol ® Ultrez 10, 20, 21 NF polymer, carbopol ® 971P NF polymer, carbopol 980 homopolymer C polymer, carbopol 980 NF polymer, carbobol ® 980P Polymer, carbopol ® ETD 2020 NF polymer, carbopol 71G NF polymer, carbopol ® 981P NF polymer, carbopol ® 970P NF polymer, carbopol ® 981P NF polymer, carbopol ® 5984P NF Polymer, carbopol ® 934P NF Polymer, carbopol ® 940P NF Polymer, carbopol ® 941P NF Polymer, carbopol ® 13242 NF polymers, carbopols ® AA-1 USP NF polymer, carbopol ® TR1 NF polymers, carbopol ® TR2 NF polymer, lubrizol Aqua CC polymer and SF-2 polymer, and any combination thereof.
In some embodiments, the first composition may comprise cellulose, such as, but not limited to, carboxymethyl cellulose or a salt thereof. In some embodiments, the first composition may comprise sodium carboxymethyl cellulose.
In some embodiments, the adhesion promoter present in the first composition may be a polymer comprising acidic groups, such as, but not limited to, carboxylic acid groups. The acidic groups of the polymer may be partially neutralized in the first composition. In certain embodiments, the tackifier present in the first composition may be carboxypolyethylene. In some embodiments, the carboxypolyethylene present in the first composition may be partially neutralized. The first composition may comprise carboxypolyethylene and have a pH of about 3 to about 7, about 3.5 to about 6.5, about 3.5 to about 6, or about 4 to about 6. In certain embodiments, the first composition may comprise carboxypolyethylene and have a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, or 7.
A tackifier may be present in the first composition. In some embodiments, the compositions of the present invention may comprise at least two tackifiers, which may be the same or different. In some embodiments, the first tackifier may be present in the first composition in an amount of from about 0.01% to about 5% by weight of the first composition or any range and/or individual value therein, such as, but not limited to, from about 0.05% to about 3%, from about 1% to about 5%, from about 1% to about 3%, or from about 0.1% to about 1.5% by weight of the first composition. In certain embodiments, the first tackifier is present in the first composition in an amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% by weight of the first composition or any range and/or individual value therein.
The water may be present in the first composition in an amount of about 55% to about 99% by weight of the first composition or any range and/or individual value therebetween, such as, but not limited to, about 55% to about 75%, about 60% to about 95%, about 60% to about 80%, about 75% to about 95%, or about 80% to about 90% by weight of the first composition. In certain embodiments, water is present in the first composition in an amount of about 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by weight of the first composition or any range and/or individual value therebetween.
In some embodiments, one or more solvents other than water may be present in the first composition. For example, the first composition may comprise water and 1, 2, 3, 4, 5 or more additional solvents. The one or more solvents other than water may each be present in the first composition in an amount of from about 0.5% to about 20% by weight of the first composition or any range and/or individual value therebetween, such as, but not limited to, from about 1% to about 15%, from about 1% to about 10%, from about 5% to about 15%, or from about 1% to about 5% by weight of the first composition. In certain embodiments, the one or more solvents other than water may each be present in the first composition in an amount of about 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% by weight of the first composition or any range and/or individual value therebetween. Exemplary solvents other than water that may be present in the first composition include, but are not limited to, alcohols, such as isopropyl alcohol or ethanol.
In some embodiments, the first composition comprises, consists essentially of, or consists of at least one polyol present in an amount of from about 1% to about 30% by weight of the first composition, at least one tackifier present in an amount of from about 0.1% to about 5% by weight of the first composition, and water present in an amount of from about 55% to about 99% by weight of the first composition. In certain embodiments, the tackifier may be carboxypolyethylene or carboxymethyl cellulose or a salt thereof. The first composition may be a hydrogel.
The first composition may comprise a preservative. The preservative may be present in the first composition in an amount of about 0.01% to about 1% by weight of the first composition or any range and/or individual value therebetween, such as, but not limited to, about 0.01% to about 0.1%, about 0.05% to about 0.5%, about 0.05% to about 1%, or about 0.1% to about 1% by weight of the first composition. In certain embodiments, the preservative is present in the first composition in an amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1% by weight of the first composition or any range and/or individual value therebetween. Exemplary preservatives that may be present in the first composition include, but are not limited to, sorbic acid, benzoic acid, methyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl chloroisothiazolinone, methyl alcohol isothiazolinone (metholisothiazolinone), bisimidazolidinyl urea, chlorobutanol, triclosan, benzethonium chloride, parahydroxybenzoate, chlorhexidine, digluconate, isoxadifen cetyl trimethylammonium bromide, alcohols, benzalkonium chloride, boric acid, bronopol, butyl p-hydroxybenzoate, calcium butylene acetate, calcium chloride, calcium lactate, carbon dioxide, cations and bentonite, cetyl trimethylammonium bromide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, citric acid monohydrate, cresol, dimethyl ether, ethyl p-cyanobenzoate, glycerol, hexetidine, imidurea, isopropyl alcohol, lactic acid, monothioglycerol, pentetic acid, phenol, phenoxyethanol, phenethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium sorbate, propionic acid, propyl gallate, propylene glycol, sodium acetate, sodium benzoate, sodium borate, sodium lactate, sodium sulfite, sodium propionate, sodium metabisulfite, xylitol, sulfur dioxide, carbon dioxide, and any combination thereof.
The first composition may comprise a neutralizing agent. The neutralizing agent may be present in the first composition in an amount sufficient to provide the desired pH, such as, but not limited to, a pH of about 3 to about 11, or any range and/or individual value therebetween, such as, but not limited to, about 3 to about 8, about 4 to about 7, or about 6 to 11.
In some embodiments, the neutralizing agent may be present in the first composition in an amount sufficient to provide the first composition with a pH in the range of about 3 to about 8.
In certain embodiments, the neutralizing agent can be present in the first composition in an amount sufficient to provide a composition of the invention having a desired pH when the first composition and the second portion (e.g., the second composition) are combined and/or when the first composition and/or the composition comprising the first composition and the second portion are administered to the skin of a subject. The neutralizing agent can be present in the first composition in an amount sufficient to provide the composition of the invention (e.g., a composition comprising the first composition and the second composition) with a desired pH, such as, but not limited to, a pH of about 3 to about 11, or any range and/or individual value therebetween.
In some embodiments, the neutralizing agent adjusts the pH of the first composition and/or the composition of the present invention. In certain embodiments of the invention, the neutralizing agent is present in the first composition in an amount sufficient to provide the first composition with a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 or any range and/or individual value therebetween. In some embodiments of the invention, the neutralizing agent is present in the compositions of the invention in an amount sufficient to provide the composition with a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, or 11, or any range and/or individual value therebetween.
Exemplary neutralizing agents that may be present in the first composition include, but are not limited to, bases (e.g., sodium hydroxide, potassium hydroxide, and mixtures thereof), acids (e.g., hydrochloric acid, citric acid, lactic acid, glycolic acid, acetic acid, and mixtures thereof), sodium carbonate, triethanolamine, tromethamine, aminomethylpropanol, triisopropanolamine, aminomethylpropanol, tetrahydroxypropyl ethylenediamine, tetrasodium EDTA, sumtocide a, and any combination thereof.
The neutralizing agent may be present in the first composition in an amount of about 0.01% to about 1% by weight of the first composition or any range and/or individual value therebetween, such as, but not limited to, about 0.01% to about 0.1%, about 0.05% to about 1%, or about 0.1% to about 1% by weight of the first composition. In certain embodiments, the neutralizing agent may be present in the first composition in an amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% by weight of the first composition or any range and/or individual value therebetween.
The first composition may be unbuffered or buffered. In some embodiments, the first composition may be unbuffered. In other embodiments, the first composition may be buffered. Exemplary buffers that may be present in the first composition include, but are not limited to, acetic acid/acetate buffer, hydrochloric acid/citrate buffer, phosphate buffer, citrate/citrate buffer, lactate buffer, tartrate buffer, malate buffer, glycine/HCl buffer, saline buffer (e.g., phosphate Buffered Saline (PBS), tris-buffered saline (TBS), tris-HCl, naCl, tween buffered saline (TNT), phosphate buffered saline, triton X-100 (PBT), and mixtures thereof), dimethylarsenate buffer, barbital buffer, tris buffer, and any combination thereof. In some embodiments, the buffer may be a phosphate buffer, for example, dipotassium hydrogen phosphate and/or potassium dihydrogen phosphate buffer.
In some embodiments, the buffer may be present in the first composition in an amount of about 0.01% to about 20% by weight of the first composition or any range and/or individual value therebetween, such as, but not limited to, about 0.1% to about 20%, about 1% to about 15%, about 5% to about 20%, about 10% to about 20%, or about 1% to about 10% by weight of the first composition. In certain embodiments, the buffer is present in the first composition in an amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% by weight of the first composition or any range and/or individual value therebetween.
In certain embodiments, the first composition may comprise a buffer. Exemplary buffers include, but are not limited to, citric acid, acetic acid, lactic acid, boric acid, succinic acid, malic acid, and any combination thereof. The buffer may be present in the first composition in an amount of about 0.01% to about 4% by weight of the first composition or any range and/or individual value therebetween, such as, but not limited to, about 0.01% to about 0.1%, about 0.05% to about 1%, about 0.1% to about 0.5%, about 1% to about 3%, or about 0.1% to about 2% by weight of the first composition. In certain embodiments, the buffer is present in the first composition in an amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.25%, 3.5%, 3.75% or 4% by weight of the first composition or any range and/or individual value therebetween.
In some embodiments, the buffer and/or buffer is present in the first composition in an amount sufficient to provide the first composition with a pH of about 3 to about 8 or any range and/or individual value therebetween, such as, but not limited to, about 3 to about 6, about 3 to about 5, about 4 to about 7, about 5 to about 7, or about 6 to about 7. In certain embodiments of the invention, the buffer and/or buffer may be present in the first composition in an amount sufficient to provide the first composition with a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8, or any range and/or individual value therebetween.
In some embodiments, the buffer and/or buffer may be present in the first composition in an amount sufficient to provide the desired pH to the composition of the invention comprising the first composition and the second portion (e.g., the second composition). For example, the compositions of the present invention may comprise a second composition and a first composition comprising a buffer and/or buffer, wherein the buffer and/or buffer is present in an amount sufficient to provide a composition having a pH of from about 3 to about 11, such as, but not limited to, from about 3 to about 8, from about 7 to about 11, from about 8 to about 10, from about 3 to about 5, from about 4 to about 7, from about 5 to about 7, or from about 6 to about 7. In certain embodiments of the invention, the buffer and/or buffer may be present in the first composition in an amount sufficient to provide the composition of the invention with a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, or 11, or any range and/or individual value therebetween. In some embodiments, the buffer and/or buffer may be present in the first composition in an amount sufficient to provide a desired pH when administered to the skin of a subject comprising the first composition and the second portion of the composition of the invention.
In some embodiments, the buffer, and/or neutralizing agent may be present in the first composition in an amount sufficient to provide the composition of the invention and/or the first composition with the desired pH.
In some embodiments, emollients such as, but not limited to, silicones, e.g., cyclomethicone, dimethicone, C26-28 alkyl methicone, polyphenylsilsequioxane, trimethylsiloxysilicate, and copolymers of cyclopentasiloxane and dimethicone/vinyltrimethylsiloxysilicate, and mixtures thereof, may be provided in the first composition. In some embodiments, the first composition may comprise cyclomethicone. The emollient may be present in the first composition in an amount of about 0.5% to about 10% by weight of the first composition or any range and/or individual value therebetween, such as, but not limited to, about 1% to about 5%, about 0.5% to about 4%, about 1% to about 10%, or about 2% to about 8% by weight of the first composition. In certain embodiments, the emollient may be present in the first composition in an amount of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by weight of the first composition or any range and/or individual value therebetween.
In certain embodiments, the first composition may comprise at least one polyol present in an amount of about 1% to about 30% by weight of the first composition, at least one adhesion promoter present in an amount of about 0.01% to about 5% by weight of the first composition, water present in an amount of about 55% to about 99% by weight of the first composition, and optionally at least one preservative present in an amount of about 0.01% to about 1% by weight of the first composition. The first composition may have a pH ranging from about 3 to about 8, from about 3 to about 6, or from about 6 to about 8 and may be buffered. The first composition may be a hydrogel.
In some embodiments, the first composition may comprise, consist essentially of, or consist of a polyol in an amount of about 1% to about 15% by weight of the first composition, a tackifier in an amount of about 0.1% to about 5% by weight of the first composition, water in an amount of about 55% to about 85% by weight of the first composition, optionally a buffer in an amount of about 0.1% to about 20%, optionally a buffer in an amount of about 0.001% to about 2% by weight of the first composition, optionally a preservative in an amount of about 0.001% to about 1% by weight of the first composition, and optionally a neutralizing agent in an amount of about 0.001% to about 1% by weight of the first composition. The first composition may have a pH in the range of about 3 to about 5 or about 5 to about 7. In certain embodiments, the tackifier present in the first composition may be carboxypolyethylene or carboxymethyl cellulose or a salt thereof. In some embodiments, the first composition may be cosmetically elegant (cosmetically elegant). The first composition may be a hydrogel.
In some embodiments, the first composition may comprise, consist essentially of, or consist of a polyol in an amount of about 1% to about 30% by weight of the first composition, a tackifier in an amount of about 0.01% to about 5% by weight of the first composition, water in an amount of about 55% to about 99% by weight of the first composition, at least one additional solvent (e.g., alcohol) in an amount of optionally about 0.5% to about 20% by weight of the first composition, an emollient in an amount of optionally about 0.5% to about 10% by weight of the first composition, a buffer in an amount of optionally about 0.01% to about 20% by weight of the first composition, a preservative in an amount of optionally about 0.001% to about 1% by weight of the first composition, and a neutralizing agent in an amount of optionally about 0.001% to about 1% by weight of the first composition. In some embodiments, the at least one solvent comprises an alcohol and the first composition comprises a buffer, an emollient, and a preservative. The first composition may have a pH in the range of about 3 to about 5 or about 5 to about 7. In some embodiments, the pH may be about 4.5. In certain embodiments, the tackifier present in the first composition may be carboxymethyl cellulose or a salt thereof. In some embodiments, the first composition may be cosmetically elegant. The first composition may be a hydrogel.
The compositions of the present invention may comprise an Active Pharmaceutical Ingredient (API). In addition to the acidified nitrite, any suitable API or combination of APIs may be included in the compositions of the present invention. In some embodiments, the API may be any suitable API that provides for nitric oxide release as described herein. Examples of APIs include, but are not limited to, antimicrobial agents, anti-acne agents, anti-inflammatory agents, analgesic agents, anesthetic agents, antihistamines, antiseptic agents, immunosuppressants, hemostatic agents, vasodilators, wound healing agents, anti-biofilm agents, and any combination thereof. Exemplary APIs include, but are not limited to, those described in international application publication No. WO 2013/006608, which is incorporated herein by reference in its entirety.
In some embodiments, the first composition may not include an API. In certain embodiments, the first composition does not comprise a Nitric Oxide (NO) release API. In some embodiments, the first composition may comprise at least one API, but the first composition may not comprise NO-release API. In some embodiments, the first composition comprises an API (e.g., humidity sensitive API) and the second composition comprises a second API, e.g., NO-release API.
In some embodiments, the second composition may be an anhydrous composition. As used herein, "anhydrous" means that no water is added directly to the second composition when prepared. However, one of skill in the art will recognize that the second composition and/or one or more components of the second composition may physically and/or chemically absorb water (i.e., indirectly add water to the second composition) at any time during the preparation, storage, and/or use of the second composition. In some embodiments, the term "anhydrous" means that the second composition has a water content of less than 5% by weight of the second composition or any range and/or individual value therebetween. The second composition may have a water content of less than 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1 or 0.5%, or any range therebetween, by weight of the second composition. The water content may be measured by methods known to those skilled in the art, such as, but not limited to, karl Fischer titration. In certain embodiments, the composition of the present invention, upon contact with the second composition, adds water to the second composition and/or the second composition absorbs water from the composition of the present invention.
Exemplary second compositions that can be used and/or placed in contact with the first composition include, but are not limited to, those described in international application publication number WO 2013/006608, which is incorporated herein by reference in its entirety. An exemplary second composition that may be used in contact with and/or placed in order to form the topical antiviral composition of the present invention may comprise an anhydrous composition comprising at least one adhesion promoter present in the second composition in an amount of from about 0.1% to about 30% by weight of the second composition, at least one organic solvent present in the second composition in an amount of from about 50% to about 90% by weight of the second composition, and at least one humectant present in the second composition in an amount of from about 2% to about 20% by weight of the second composition. The second composition may further comprise at least one water repellent, also known as a water repellent.
Exemplary tackifiers for use in the second composition include, but are not limited to, copolymers of carboxymethyl cellulose with acrylic acid, N-vinyl pyrrolidone, polyalkylene glycols (e.g., poly (ethylene glycol)), polyalkylene oxides (e.g., polyethylene oxide), polyvinyl alcohol, polyvinyl pyrrolidone, polysiloxanes, poly (ethylene acetate), cellulose, derivatized cellulose, alginates, copolymers thereof, and mixtures thereof. Specific examples of the tacky agent for the second composition are hydroxypropyl cellulose, such as Klucel-hydroxypropyl cellulose (e.g., klucel ® MF pharmaceutical grade). The tackifier may be present in the second composition in an amount of from about 0.1% to about 30% by weight of the second composition or any range and/or individual value therebetween, such as, but not limited to, from about 0.5% to about 20%, from about 0.1% to about 2%, from about 0.5% to about 5%, from about 1% to about 10%, or from about 1% to about 5% by weight of the second composition. In certain embodiments, the tackifier may be present in the second composition in an amount of about 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30% by weight of the second composition or any range and/or individual value therebetween.
Exemplary organic solvents for the second composition include, but are not limited to, acetone, methanol, ethanol, isopropanol, butanol, ethyl acetate, dimethyl isosorbide, propylene glycol, glycerin, ethylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, or mixtures thereof. In some embodiments of the invention, the organic solvent in the second composition may be ethanol and/or isopropanol. The organic solvent may be present in the second composition in an amount of about 40% to about 90% by weight of the second composition or any range and/or individual value therebetween, such as, but not limited to, about 40% to about 80%, about 50% to about 70%, about 50% to about 80%, about 60% to about 90%, about 70% to about 90%, or about 75% to about 85% by weight of the second composition. In certain embodiments, the organic solvent may be present in the second composition in an amount of about 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% by weight of the second composition or any range and/or individual value therebetween.
Exemplary humectants for use in the second composition include, but are not limited to, glycols, such as diethylene glycol monoethyl ether, glycerol; sugar polyols such as sorbitol, xylitol and maltitol; polyols such as polydextrose; quillaja saponaria, urea, and mixtures thereof. In some embodiments, the humectant in the second composition may include an alkylene glycol, for example, hexylene glycol. The humectant may be present in the second composition in an amount of from about 2% to about 20% by weight of the second composition or any range and/or individual value therebetween, such as, but not limited to, from about 2% to about 15%, from about 5% to about 15%, or from about 15% to about 20% by weight of the second composition. In certain embodiments, the humectant may be present in the second composition in an amount of about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% by weight of the second composition, or any range and/or individual value therebetween.
Exemplary water repellents for the second composition include, but are not limited to, silicones such as cyclomethicone, dimethicone, C26-28 alkyl silicone oil, polyphenylsilsequioxane, trimethylsiloxysilicate, and copolymers of cyclopentasiloxane and dimethicone/vinyl trimethylsiloxysilicate, and mixtures thereof. In some embodiments, the second composition may comprise cyclomethicone. The water-repellent agent may be present in the second composition in an amount of about 0.5% to about 15% by weight of the second composition or any range and/or individual value therebetween, such as, but not limited to, about 0.5% to about 10%, about 1% to about 5%, or about 2% to about 5% by weight of the second composition. In certain embodiments, the water-repellent agent may be present in the second composition in an amount of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% by weight of the second composition or any range and/or individual value therebetween.
Thus, the topical antiviral compositions of the present invention can comprise at least one polyol, a first tackifier, water, a second tackifier, at least one organic solvent, at least one humectant, optionally at least one solvent other than water, optionally an emollient, optionally a water repellant, optionally at least one preservative, and optionally at least one buffer and/or buffer. The composition may be buffered to a pH of about 3 to about 11, such as, but not limited to, about 6 to about 10, about 7 to about 10, or about 7 to about 9. In some embodiments, the composition may have a pH of 7 or greater, 7.5 or greater, or 9.5 or greater. In certain embodiments, the composition may comprise at least one API, such as, but not limited to, nitric oxide-releasing active pharmaceutical ingredient. In some embodiments, the NO-release API may be a diazeniumdiolate modified macromolecule.
The topical antiviral compositions of the present invention can comprise a first composition and a second composition as described herein. As will be appreciated by those skilled in the art, the amount or concentration of each component in the compositions of the present invention can vary depending on the amount of the first composition and the second composition present in the composition (e.g., the ratio of the first composition to the second composition in the composition). In some embodiments, the ratio of the first composition to the second composition of the present invention in the composition of the present invention may be about 5:1 or less, in further embodiments about 4:1 or less, about 3:1 or less, about 2:1 or less, about 1:1 or less, about 0.5:1 or less, or about 0.2:1 or less. In particular embodiments, the ratio may be about 3:1. In further embodiments, the ratio may be about 1:1.
In some embodiments, the compositions of the present invention may comprise, consist of, or consist essentially of, a polyhydric alcohol in an amount of from about 0.5% to about 10% by weight of the composition, a first adhesion promoter in an amount of from about 0.01% to about 3% by weight of the composition, water in an amount of from about 30% to about 50% by weight of the composition, at least one solvent other than water in an amount of from about 0.5% to about 10% by weight of the composition, an emollient in an amount of from about 0.5% to about 5% by weight of the composition, a buffer in an amount of from about 0.01% to about 10% by weight of the composition, a second adhesion promoter in an amount of from about 0.01% to about 10% by weight of the composition, an organic solvent in an amount of from about 20% to about 45% by weight of the composition, a humectant in an amount of from about 2% to about 10% by weight of the composition, a NO-release API in an amount of from about 0.1% to about 10% by weight of the composition, a buffer in an amount of from about 0.5% to about 25% by weight of the composition, an optional amount of from about 0.001% to about 1% by weight of the composition, an optional preservative in an amount of about 0.001% to about 1% by weight of the composition, an optional amount of the composition and an optional. The buffer, and/or neutralizing agent may be present in an amount sufficient to provide a first portion of the composition having a pH of about 3 to about 8. The composition may have a pH of less than about 11, such as, but not limited to, less than about 9.5, less than about 7, or less than about 6. In some embodiments, the composition may have a pH of about 4.5. The first and second tackifiers may be the same and/or different. In certain embodiments, the first tackifier may be carboxypolyethylene and the second tackifier may be cellulose, such as, but not limited to, hydroxypropyl cellulose. In some embodiments, the first tackifier may be carboxymethyl cellulose or a salt thereof, and the second tackifier may be cellulose, such as, but not limited to, hydroxypropyl cellulose. In some embodiments, the composition may be cosmetically elegant.
In some embodiments, the compositions of the present invention may comprise, consist of, or consist essentially of, a polyhydric alcohol in an amount of from about 1% to about 7% by weight of the composition, a first adhesion promoter in an amount of from about 0.1% to about 3% by weight of the composition, water in an amount of from about 25% to about 40% by weight of the composition, at least one solvent other than water in an amount of from about 0.5% to about 10% by weight of the composition, an emollient in an amount of from about 0.5% to about 5% by weight of the composition, a buffer in an amount of from about 0.01% to about 10% by weight of the composition, a second adhesion promoter in an amount of from about 0.1% to about 2% by weight of the composition, an organic solvent in an amount of from about 20% to about 45% by weight of the composition, a humectant in an amount of from about 2% to about 7% by weight of the composition, a water-repellent in an amount of from about 1% to about 5% by weight of the composition, a NO-release API in an amount of from about 5% to about 20% by weight of the composition, optionally a buffer in an amount of from about 0.01% to about 0.2% by weight of the composition, optionally a preservative in an amount of about 0.01% to about 0.3% by weight of the composition, and optionally. The buffer, and/or neutralizing agent may be present in an amount sufficient to provide a first portion of the composition having a pH of about 4 or about 6. The composition may have a pH of less than about 11, such as, but not limited to, less than about 9.5, less than about 7, or less than about 6. In some embodiments, the composition may have a pH of about 4.5. The first and second tackifiers may be the same and/or different. In certain embodiments, the first tackifier may be carboxypolyethylene and the second tackifier may be cellulose, such as, but not limited to, hydroxypropyl cellulose. In some embodiments, the first tackifier may be carboxymethyl cellulose or a salt thereof, and the second tackifier may be cellulose, such as, but not limited to, hydroxypropyl cellulose. In some embodiments, the composition may be cosmetically elegant. In certain embodiments, the composition may comprise the compositions as listed in table 2 and/or table 13.
In some embodiments, the compositions of the present invention may comprise or consist essentially of a polyol in an amount of from about 1% to about 15% by weight of the composition, a first adhesion promoter in an amount of from about 0.01% to about 2.5% by weight of the composition, water in an amount of from about 25% to about 50% by weight of the composition, at least one additional solvent (e.g., alcohol) in an amount of from about 0.5% to about 10% by weight of the composition, an emollient in an amount of from about 0.5% to about 5% by weight of the composition, a buffer in an amount of from about 0.01% to about 10% by weight of the composition, a second adhesion promoter in an amount of from about 0.01% to about 10% by weight of the composition, an organic solvent in an amount of from about 20% to about 50% by weight of the composition, a humectant in an amount of from about 2% to about 10% by weight of the composition, a water-repellent in an amount of from about 0.1% to about 10% by weight of the composition, a NO-release API in an amount of from about 0.5% to about 25% by weight of the composition, and a preservative in an amount of from about 0.001% to about 0.5% by weight of the first composition.
The compositions of the present invention may comprise at least two different adhesion promoters. A tackifier may be present in a first part of the composition of the present invention and another tackifier may be present in a second part of the composition. In some embodiments, the compositions of the present invention comprise carboxypolyethylene and cellulose, such as, but not limited to, hydroxypropyl cellulose. Carboxypolyethylene may be present in a first composition of the invention and cellulose may be present in a second composition, both of which may be combined to form a composition of the invention. In some embodiments, the compositions of the present invention comprise sodium carboxymethyl cellulose and a second cellulose, such as, but not limited to, hydroxypropyl cellulose. Sodium carboxymethyl cellulose may be present in a first composition of the invention and a second cellulose may be present in a second composition, the two compositions may be combined to form a composition of the invention. The compositions of the present invention comprising at least two different adhesion promoters may provide cosmetically elegant compositions comprising an API, such as, but not limited to, a particulate API and/or an insoluble API (e.g., an aqueous and/or water insoluble API, such as benzoyl peroxide).
The compositions of the present invention may comprise API, sodium carboxymethyl cellulose, and hydroxypropyl cellulose, and may be cosmetically elegant compositions. The composition may not be sandy and/or may have a reduced sandiness as compared to the API in the absence of the composition of the invention. The composition may be non-tacky (i.e., sticky) and/or may have a reduced tackiness (i.e., viscosity) as compared to an API in the absence of the composition of the invention. The composition may have reduced and/or increased stiffness (i.e., hardness) and/or may have increased homogeneity as compared to an API in the absence of the composition of the invention. In some embodiments, the compositions of the present invention may comprise an API and may be cosmetically elegant homogenous compositions.
According to embodiments of the present invention, the topical antiviral composition may be provided in a kit. In some embodiments, the kits of the invention may comprise a first composition and a second composition as described herein that can be combined to form a topical antiviral composition. The kit may store the first and second compositions separately. The kit may be configured to mix the two compositions at a desired ratio (e.g., 1:1, 2:1, etc.) upon dispensing and/or application to the skin of a subject.
The invention is explained in more detail in the following non-limiting examples.
Examples
Example 1
Rabbit groups received different doses of antiviral treatment, as described in table 1 below. Formulations for antiviral treatment in groups a-G are provided in tables 2 and 3. Each formulation for groups a-E contained two separate compositions stored separately in a dual chamber pump. Prior to administration, the two compositions were dispensed at a 1:1 ratio and mixed together to provide a combined composition for administration to rabbits. The target pH of the combined composition was pH 8.
Table 1: antiviral treatment dosage
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Table 2: formulations for antiviral treatment in groups A-E
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Table 3: formulations for antiviral treatment in groups F and G
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For early therapeutic antiviral treatment studies rabbits were infected with wild-type cotton-tail rabbit papillomavirus (wt CRPV) and E8-knockdown CRPV (mE 8-CRPV) starting from the first day. Figure 1 shows a schematic representation of experimental infection. mE8-CRPV is included because this genome produces smaller, slower-growing papillomas that are more clinically similar to human papillomavirus infection.
A total of 32 adult new zealand white rabbits (including both sexes) were purchased from Robinson, PA and used in this experiment. Rabbits were quarantined and cleaned (14 days). Each rabbit was vaccinated with wt CRPV (at 2 sites; 5. Mu.g/site) and mE8-CRPV viral DNA (at 2 sites; 5. Mu.g/site). CRPV viral DNA is used to produce papillomas, infection is achieved via delayed scarification techniques (Cladel n.m., et al, J Virol Methods 2008; 148 (1-2): 34-39). Of the two sites inoculated with one virus, one site was treated (i.e., left site (L1 or L2)) and the other site was not treated (i.e., right site (R1 and L2)R2))。
Rabbits were placed into one of eight groups (groups a-H). The placebo group (i.e., group a) was used as a control to evaluate the local effects of the treatments in treatment groups B-H. Groups B-G represent test compounds compared to placebo negative control.
Treatment of groups a-H began the second week when papillomas were not yet visible. This time point allows evaluation of the effect on subclinical papillomas. Treatment was performed 5 times per week (monday-friday) for 5 weeks at a dose of 0.1 ml per approximately 2.5 cm X2.5 cm locus for topical treatment. Body weight was obtained weekly, as required, and serum was collected for blood chemistry at the end of the treatment period.
Papilloma frequency and size were measured in mm on 3 axes (length x width x height) per week. The data were entered into a spreadsheet and calculations were made for plots of the geometric mean diameter of each papilloma, mean ± SEM of each group, student's t test between each pair of groups, and papilloma size vs. time composition. Body weight changes were also plotted.
At termination, kidney and liver samples were retrieved as needed for histological and toxicity assessment. The skin/papilloma sites were monitored with photographs and biopsies were taken to assess histology at the termination of the experiment/treatment.
Figures 2-9 show plots of mean (±sem) of GMD measurements plotted against time after CRPV infection for each treatment group. For the calculation of average GMD, no spontaneous regression was used in group D. Figure 10 shows the average body weight of the treatment group.
As seen in FIG. 2, gel carriers without NO-releasing API provided little to NO differentiation in papilloma size between treated and untreated sites for wild type or mE8-CRPV mutant papilloma virus sites. In fig. 3, the 1% niticil ™ NVN group shows some differences between the treated and untreated sites for the mutant. However, complete inhibition of papilloma growth is not achieved. In fig. 4, group 1.6% niticil ™ NVN shows little distinction between treated and untreated sites for wild-type virus and mutant. Figure 5 shows that 10% of Nitricil ™ NVN1 is effective in treating both wild-type virus and mutant strains in which papilloma growth is completely inhibited, with a clear distinction between treated and untreated sites in the more rapidly growing wild-type. Figure 6 shows that 16.3% of niticil ™ NVN4 effectively inhibited mutant growth but not wild-type virus growth. As seen in fig. 7, for wild-type or mutant papillomavirus sites, the NO-release API-free ointment carrier provided little differentiation in papilloma size between treated and untreated sites. As seen in fig. 8, for either wild-type or mutant papillomavirus sites, 10% NVN1 ointment provided little differentiation in papilloma size between treated and untreated sites, demonstrating that release of nitric oxide from the composition affects the effectiveness of inhibiting papilloma growth, as opposed to the presence of a siloxane scaffold, as both 10% NVN1 ointment and 10% NVN1 gel contained the same amount of polysiloxane scaffold but achieved significantly different results.
Example 2
In vitro release assays were performed using a multichannel nitric oxide analyzer. The test formulations of groups B-E and G described in example 1 were weighed using an analytical balance. About 20 mg of each formulation was transferred in two phases to a clean, dry NO measurement cell with a magnetic stirrer bar. The real-time in vitro release of nitric oxide from the formulation was measured while mixing continuously using the following instrument parameters:
1. wet nitrogen flow rate: 112-115 ml/min
2. Sample temperature: 37 DEG C
3. And (3) detection: detection of nitric oxide by chemiluminescence
4. Data acquisition frequency: 1 Hz, irregular order alternating
5. Duration of time: time of linear decrease in NO Release Rate (NLT 8 hr)
6. And (3) acquisition software: novanWare
Conversion of Parts Per Billion (PPB) NO to molar nitric oxide is achieved by measuring the nitric oxide produced from a known amount of sodium nitrite in a potassium iodide solution to obtain the PPB to molar conversion factor. Any gaps in the real-time nitric oxide release data resulting from the multi-channel operation are filled using a linear interpolation procedure. For any samples not measured to be depleted of nitric oxide, a linear extrapolation of the last to 5000 seconds release was performed to zero release. However, the method is thatThe real-time nitric oxide release data is post-integrated to produce a total nitric oxide accumulation curve. Nitric oxide release parameters such as C max (i.e., maximum concentration of NO released), T max (i.e. reach C max Time of cumulative nitric oxide release (i.e., sum of all data points per unit time), and time of half total release (T) 50 ) (i.e., the time to release 50% of the cumulative NO) can be calculated from both the real-time and the aggregate cumulative nitric oxide release profile. All of the above calculations are performed automatically in custom data processing software (NovanWare).
The results of the in vitro release assay, along with the respective pH of the mixtures, are summarized in table 4 below.
Table 4: NO release data of test reagent
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Example 3
The test article of example 2 was applied to the 2.5 cm X2.5 cm site of the rabbit of example 1. 6.25 to 6.25 cm 2 Administration of the 0.1 mL test results in NO/cm as reflected in Table 5 2 Release is determined in vitro.
Table 5: NO release data per unit area for the formulations tested
Figure DEST_PATH_IMAGE010
The real-time and cumulative NO release profile is illustrated in fig. 11-17 as described above. Based on the effectiveness of the formulations for treatment groups D and E against mutants, real-time NO release parameters that are antiviral can be identified as illustrated in fig. 16A, 16B and 17. Thus, in some embodiments of the invention, NO release from the antiviral composition may fall into one or more of the windows illustrated in fig. 16A and/or 17. NO release within the defined window may occur at any point in time within the expected time that the composition will be administered. Thus, NO release falling within the window may occur within the first 1, 2 or 4 hours or may begin to occur at another time during the administration period. The time windows illustrated in fig. 16A, 16B, and 17 are shown in table 6.
Table 6: NO release time window
Window Duration of time Minimum real time NO Maximum real time NO
Weighting 0.5 hours 0.5 hour 25 pmol/mg 4000 pmol/mg
1 hour weighting 1 hour 7 pmol/mg 4000 pmol/mg
Weighting for 2 hours For 2 hours 6 pmol/mg 4000 pmol/mg
3 hour weighting 4 hours 5 pmol/mg 4000 pmol/mg
Time zone
1 hour 1 smallTime of day 74.4 nmol/cm 2 59.52 nmol/cm 2
2 hours zone For 2 hours 89.28 nmol/cm 2 59.52 nmol/cm 2
3 hours zone 4 hours 104.16 nmol/cm 2 59.52 nmol/cm 2
Example 4
Rabbit groups received different doses of antiviral treatment as described in table 7 below. Formulations for antiviral treatment in groups a-F are provided in table 8. Each formulation for groups a-E contained two separate compositions stored separately in a dual chamber pump. Prior to administration, the two compositions were dispensed at a 1:1 ratio and mixed together to provide a combined composition for administration to rabbits. The target pH of the combined composition was pH 8.
Table 7: antiviral treatment dosage
Figure DEST_PATH_IMAGE012
Table 8: formulations for antiviral treatment in groups A-E
Figure DEST_PATH_IMAGE014
Table 9: table 8 NO release data for formulations
Figure DEST_PATH_IMAGE016
For early therapeutic antiviral treatment studies rabbits were infected with wild-type cotton-tail rabbit papillomavirus (wt CRPV) and E8-knockdown CRPV (mE 8-CRPV) starting from the first day. Figure 1 shows a schematic representation of experimental infection. mE8-CRPV is included because this genome produces smaller, slower-growing papillomas that are more clinically similar to human papillomavirus infection.
A total of 24 adult new zealand white rabbits (including both sexes) were purchased from Robinson, PA and used in this experiment. Rabbits were quarantined and cleaned (14 days). Each rabbit was vaccinated with wt CRPV (at 2 sites; 5. Mu.g/site) and mE8-CRPV viral DNA (at 2 sites; 5. Mu.g/site). CRPV viral DNA is used to produce papillomas, infection is achieved via delayed scarification techniques (Cladel n.m., et al,J Virol Methods 2008; 148 (1-2): 34-39). Of the two sites vaccinated with one virus, one site received treatment (i.e., left site (L1 or L2)) and the other site did not (i.e., right site (R1 and R2)).
Rabbits were placed into one of six groups (groups a-F). The placebo group (i.e., group a) was used as a control to evaluate the local effects of the treatments in treatment groups B-E.
Treatment of groups a-F began the second week when papillomas were not yet visible. This time point allows evaluation of the effect on subclinical papillomas. Treatment was performed 5 times per week (monday-friday) for 5 weeks at a dose of 0.1 ml per approximately 2.5 cm X2.5 cm locus for topical treatment. Body weight was obtained weekly, as required, and serum was collected for blood chemistry at the end of the treatment period.
Papilloma frequency and size were measured in mm on 3 axes (length x width x height) per week. The data were entered into a spreadsheet and calculations were made for plots of the geometric mean diameter of each papilloma, mean ± SEM of each group, student's t test between each pair of groups, and papilloma size vs. time composition. Body weight changes were also plotted.
At termination, kidney and liver samples were retrieved as needed for histological and toxicity assessment. The skin/papilloma sites were monitored with photographs and biopsies were taken to assess histology at the termination of the experiment/treatment.
Figures 18-23 show plots of papilloma size (GMD) in mm versus time for the formulations in groups a-F, respectively. According to a dosing regimen of once per day 5 days per week, a dose showing only minimal efficacy may be suitable for use in a different dosing regimen, e.g. 7 days per week twice per day. Based on the effectiveness of the formulations of treatment groups D and E on the mutants, the parameters of real-time NO release may fall within one or more of the windows illustrated in fig. 16A and/or 17. However, other doses may be effective based on treatment groups B and C, as the duration of NO release for these groups may allow for more frequent dosing. Thus, products (e.g., topical compositions) having NO release falling within a 30 minute window as defined based on weight measurements and having a minimum instantaneous release of 7 pmol/mg and a maximum instantaneous release of 4,000 pmol/mg may be suitable. In some embodiments, a product with NO release falling within a 30 minute window as defined based on weight measurements and having a minimum instantaneous release of 15 pmol/mg and a maximum instantaneous release of 4,000 pmol/mg may be suitable. NO release within a defined window may occur at any point in time within the expected time that the product will be applied and/or present on the subject's skin. Thus, NO release falling within one or more of the windows illustrated in fig. 16A and/or 17 may occur within the first 1, 2, or 4 hours after administration/administration or may begin to occur at another time after administration/administration.
Example 5
Tissue samples were obtained from New Zealand white rabbits infected with cotton tail rabbit papillomavirus and treated as described in example 4 at the end of the treatment. Skin sections were treated to hematoxylin and eosin (H & E) slides and submitted for microscopic evaluation blindly. After evaluating the slides, the results are summarized into three main categories: 1) papilloma, 2) hyperplasia of significant intensity, and 3) hyperplasia of little to slight intensity. The presence of inflammatory cells was qualitatively determined. No quantitative analysis was performed. However, qualitative assessment showed similar levels of inflammation between the three classifications, with inflammation generally lower and comparable. Table 10 provides histological results from H & E staining.
Table 10: h & E histological results
Figure DEST_PATH_IMAGE018
Tissue slides assigned to class #3 (minimal to mild intensity hyperplasia) included tissue samples obtained from animals treated with 8% niticil ™ NVN1 or 10% niticil ™ NVN. No nuclear dark to bright basophilic inclusion was observed in tissue slides assigned to class #3, suggesting that treatment with high concentrations of niticil ™ NVN1, e.g., 8% or 10% of the niticil ™ NVN1 formulation, suppressed and/or inhibited viral replication without altering local infiltration of inflammatory immune cells.
Example 6
Additional formulations are prepared and used to determine the efficacy of treating and/or preventing virus-related skin conditions, such as genital warts. These formulations included niticil ™ NVN1 in an amount of 4%, 8%, 12% or 16% along with placebo. Each formulation included a hydrogel having a pH of 4.5 and a composition as provided in table 11, and a second composition in gel form having a composition as provided in table 12. When the hydrogel and gel were mixed, a composition having a combination of the compositions as provided in table 13 was obtained.
Table 11: composition of hydrogel at pH 4.5
Figure DEST_PATH_IMAGE020
Table 12: composition of gel
Figure DEST_PATH_IMAGE022
Table 13: composition of the combination
Figure DEST_PATH_IMAGE024
The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein. All publications, patent applications, patents, patent publications, and other references cited herein are incorporated by reference in their entirety for all teachings relating to the sentences and/or paragraphs in which the reference appears.

Claims (44)

1. Use of a topical composition for the manufacture of a medicament for the treatment and/or prophylaxis of a viral infection in a subject in need thereof, wherein the topical composition is suitable for administration to the skin of the subject,
Wherein the topical composition comprises a nitric oxide-releasing active pharmaceutical ingredient comprising NO-releasing co-condensed silica particles having diazeniumdiolate functionality in an amount of 2% to 20% by weight of the composition,
wherein the topical composition comprises a first composition that is a hydrogel mixed with a second composition,
wherein the second composition is an anhydrous composition and comprises a nitric oxide-releasing active pharmaceutical ingredient, hydroxypropyl cellulose as a viscosity enhancer present in an amount of 0.1% to 30% by weight of the second composition, isopropyl alcohol as an organic solvent present in an amount of 50% to 90% by weight of the second composition, hexylene glycol as a wetting agent present in an amount of 2% to 20% by weight of the second composition, and cyclomethicone as a water repellent present in an amount of 0.5% to 15% by weight of the second composition,
wherein the first composition comprises glycerol as a polyol in an amount of 1% to 15% by weight of the first composition, carboxymethylcellulose or a salt thereof as a first viscosity enhancing agent in an amount of 0.1% to 5% by weight of the first composition, water in an amount of 55% to 85% by weight of the first composition, and a buffer in an amount of 0.1% to 20%, and
Wherein the topical composition has a maximum concentration of NO release of greater than 160 pmole NO/mg as measured by a real-time in vitro release test, and wherein the topical composition maintains a real-time nitric oxide concentration of at least 7 pmole NO/mg composition for at least 1 hour after administration as measured by a real-time in vitro release test.
2. The use of claim 1, wherein the topical composition releases nitric oxide in an amount of 0.05% to 6% by weight of the composition as measured by a real time in vitro release test.
3. The use of claim 1 or 2, wherein the topical composition releases nitric oxide in an accumulated amount of 10nmol no/mg composition-1000 nmol no/mg composition over a period of 1 hour after administration of the topical composition to the skin of the subject, as measured by a real-time in vitro release test.
4. The use of claim 1 or 2, wherein the topical composition releases nitric oxide in an accumulated amount of 90nmol no/mg composition-450 nmol no/mg composition over a period of 4 hours after administration of the topical composition to the skin of the subject, as measured by a real-time in vitro release test.
5. The use of claim 1 or 2, wherein the topical composition releases nitric oxide in an accumulated amount of 180nmol no/mg composition-1000 nmol no/mg composition over a period of 24 hours after administration of the topical composition to the skin of the subject, as measured by a real-time in vitro release test.
6. The use of claim 1 or 2, wherein the topical composition provides a sustained release of nitric oxide for at least 5 hours after administration of the topical composition to the skin of a subject, as measured by a real-time in vitro release test.
7. The use according to claim 6, wherein the topical composition has an NO release in the range of 1-500pmol NO/mg composition on average during sustained release of nitric oxide, as measured by a real time in vitro release test.
8. The use of claim 1 or 2, wherein the nitric oxide-releasing active pharmaceutical ingredient releases nitric oxide in an amount of at least 50% 9 minutes or more after administration of the topical composition to the skin of the subject, based on total NO release measured 24 hours after administration and as measured by a real time in vitro release test.
9. The use of claim 1 or 2, wherein the nitric oxide-releasing active pharmaceutical ingredient releases nitric oxide in an amount of at least 50% over a period of 9 minutes to 8 hours after administration of the topical skin composition to the subject, based on total NO release measured 24 hours after administration and by a real time in vitro release test.
10. The use of claim 1 or 2, wherein the nitric oxide-releasing active pharmaceutical ingredient releases nitric oxide to the skin of the subject.
11. The use of claim 1 or 2, wherein the topical composition maintains a real-time nitric oxide concentration of at least 25 pmole no/mg composition for at least 30 minutes after administration, as measured by a real-time in vitro release assay by chemiluminescence.
12. The use of claim 1 or 2, wherein the topical composition maintains a real-time nitric oxide concentration of at least 6 pmole no/mg composition for at least 2 hours after administration, as measured by a real-time in vitro release assay.
13. The use of claim 1 or 2, wherein the topical composition maintains a real-time nitric oxide concentration of at least 5 pmole no/mg composition for at least 4 hours after administration, as measured by a real-time in vitro release assay.
14. The use according to claim 1 or 2, wherein the topical composition has a maximum concentration of NO release in the range of 160 pmole NO/mg composition-3500 pmole NO/mg composition, as measured by a real-time in vitro release test.
15. The use of claim 1 or 2, wherein the topical composition releases nitric oxide at 24 hours after administration in an accumulated amount of 300nmol no/mg composition-1000 nmol no/mg composition, as measured by a real-time in vitro release test.
16. The use of claim 1 or 2, wherein the topical composition has a half-life in the range of 9 minutes to 420 minutes, as measured by a real-time in vitro release test.
17. Use of a topical composition for the manufacture of a medicament for the treatment and/or prophylaxis of a viral infection in a subject in need thereof, wherein the topical composition is suitable for administration to the skin of the subject,
wherein the topical composition comprises a nitric oxide-releasing active pharmaceutical ingredient that releases nitric oxide to the skin of a subject and the topical composition comprises nitric oxide-releasing active pharmaceutical ingredient comprising NO-releasing co-condensed silica particles having diazeniumdiolate functionality in an amount of 2% to 20% by weight of the composition,
wherein the topical composition comprises a first composition that is a hydrogel mixed with a second composition comprising a nitric oxide-releasing active pharmaceutical ingredient,
wherein the second composition is an anhydrous composition and comprises a nitric oxide-releasing active pharmaceutical ingredient, hydroxypropyl cellulose as a viscosity enhancer present in an amount of 0.1% to 30% by weight of the second composition, isopropyl alcohol as an organic solvent present in an amount of 50% to 90% by weight of the second composition, hexylene glycol as a wetting agent present in an amount of 2% to 20% by weight of the second composition, and cyclomethicone as a water repellent present in an amount of 0.5% to 15% by weight of the second composition,
Wherein the first composition comprises glycerol as a polyol in an amount of 1% to 15% by weight of the first composition, carboxymethylcellulose or a salt thereof as a first viscosity enhancing agent in an amount of 0.1% to 5% by weight of the first composition, water in an amount of 55% to 85% by weight of the first composition, and a buffer in an amount of 0.1% to 20%, and
wherein the topical composition has a concentration of greater than 2400pmolNO/cm 2 Maximum concentration of NO released by real-time in vitro release assayMeasured, and wherein the topical composition maintains at least 104pmolNO/cm for a period of at least 1 hour after administration of the composition to the skin of a subject 2 Is measured by a real-time in vitro release test.
18. The use of claim 17, wherein the topical composition maintains at least 89pmolNO/cm for a period of at least 2 hours after administration of the composition to the skin of a subject 2 Is measured by a real-time in vitro release test.
19. The use of claim 17 or 18, wherein the topical composition maintains at least 74pmolNO/cm for a period of at least 4 hours after administration of the composition to the skin of a subject 2 Is measured by a real-time in vitro release test.
20. The use of claim 17 or 18, wherein the topical composition is at 1300nmol no/cm over a period of 4 hours after administration of the composition to the skin of a subject 2 -14000nmolNO/cm 2 Is measured by a real-time in vitro release test.
21. The use of claim 17 or 18, wherein the topical composition is at 4500nmolNO/cm over a 24 hour period after administration of the composition to the skin of a subject 2 -14000nmolNO/cm 2 Is measured by a real-time in vitro release test.
22. The use of claim 17 or 18, wherein the topical composition has at least 100pmolNO/cm after 0.5 hour after administration of the topical composition to the skin of a subject 2 At least 40pmolNO/cm 2 hours after administration of the real-time NO concentration of (C) 2 At least 25pmolNO/cm 3 hours after administration 2 And/or at least 20pmolNO/cm 4 hours after administration 2 By real-time in vitro release of NO concentrationThe measured values are checked.
23. The use of claim 1 or 17, wherein the topical composition does not comprise an acidified nitrite.
24. The use of claim 1 or 17, wherein the viral infection is caused by Cytomegalovirus (CMV), epstein barr virus, varicella Zoster Virus (VZV), vaccinia virus, monkey pox virus, herpes Simplex Virus (HSV), human herpesvirus 6 (HHV-6), human herpesvirus 8 (HHV-8), papilloma virus, molluscum contagiosum virus, capripoxvirus, smallpox virus and/or coxsackievirus.
25. The use of claim 1 or 17, wherein the viral infection is caused by papillomavirus.
26. The use of claim 1 or 17, wherein the viral infection is caused by herpes simplex type 1 and/or herpes simplex type 2.
27. The use of claim 1 or 17, wherein the viral infection infects the skin of a subject.
28. The use of claim 1 or 17, wherein the medicament prevents a viral infection in a subject.
29. The use of claim 1 or 17, wherein the medicament treats a viral infection in a subject.
30. The use of claim 1 or 17, wherein the medicament prevents and/or reduces the appearance and/or size of benign lesions.
31. The use of claim 1 or 17, wherein the medicament prevents and/or reduces the appearance and/or size of malignant lesions.
32. The use of claim 1 or 17, wherein the subject is a human.
33. The use of claim 1 or 17, wherein the topical composition is applied to virus infected skin of the subject.
34. The use of claim 33, wherein the virally infected skin comprises benign lesions.
35. The use of claim 34, wherein the virally infected skin comprises warts, ulcers, papillomas, blisters, and/or rashes.
36. The use of claim 34, wherein the virally infected skin comprises warts and further removing warts prior to administering the topical skin composition to the subject.
37. The use of claim 34, wherein the virally infected skin comprises warts and the warts are not cleared prior to administration of the topical skin composition to the subject.
38. The use of claim 1 or 17, wherein the topical composition has a pH in the range of 5-10.
39. The use of claim 1 or 17, wherein the topical composition has a pH in the range of 6-8.
40. The use of claim 1 or 17, wherein the second composition further comprises:
a second tackifier;
at least one organic solvent; and
at least one wetting agent.
41. The use of claim 1 or 17, wherein the first composition and the second composition comprise two compositions that are mixed together before and/or during administration.
42. The use of claim 1 or 17, wherein the medicament prevents and/or reduces the appearance and/or size of warts.
43. The use of claim 1 or 17, wherein the basal layer and/or basal membrane 1x10 of the epithelium is administered to the subject -5 M-1x10 -7 Nitrogen oxide in an amount of M.
44. The use of claim 1 or 17, wherein the viral infection is caused by an infectious soft wart virus.
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